Cycloalkyl-linked diheterocycle derivatives

ABSTRACT

The present invention relates to compounds of formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             or pharmaceutically acceptable salts thereof, wherein A, L, D, R 1 -R 15 , w, x, y, and z are defined herein. The novel cycloalkyl-linked diheterocycle derivatives that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. The present invention also relates to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 16/157,618, filed Oct. 11, 2018, which is a continuation applicationof U.S. application Ser. No. 15/826,027, filed Nov. 29, 2017, now U.S.patent Ser. No. 10/125,130, issued on Nov. 13, 2018, which is acontinuation of U.S. application Ser. No. 15/306,979, filed Oct. 26,2016, which is a § 371 filing of PCT/IB2015/052833 filed Apr. 17, 2015,which claims the benefit of priority to U.S. Provisional Application No.61/986,876 filed Apr. 30, 2014; the entire contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel cycloalkyl-linked diheterocyclederivatives that are useful in the treatment of abnormal cell growth,such as cancer, in mammals. The present invention also relates topharmaceutical compositions containing the compounds and to methods ofusing the compounds and compositions in the treatment of abnormal cellgrowth in mammals.

BACKGROUND OF THE INVENTION

Tumor cells require nutrients to generate ATP and macromolecules tosustain survival and proliferation. (Ward P. S., et al., “MetabolicReprogramming: a Cancer Hallmark even Warburg did not Anticipate”,Cancer Cell. 21(3) (2012), pp. 297-308.) Glucose and glutamine are twomajor sources of nutrients that tumor cells depend on. Tumor cellsprefer to use glycolysis pathways, even under aerobic conditions, tometabolize glucose to produce lactic acid and ATP, the so-calledWarburg's effect. In addition to glucose, many tumor cells are addictedto glutamine (“Gln”) for survival (DeBerardinis R. J., et al., “Q'sNext: The Diverse Functions of Glutamine in Metabolism, Cell Biology andCancer”, Oncogene. 29(3) (2010), pp. 313-24; Shanware N. P., et al.,“Glutamine: Pleiotropic Roles in Tumor Growth and Stress Resistance”, JMol Med (Berl). 89(3) (2011), pp. 229-36.). This amino acid can bemetabolized to generate intermediates of tricarboxylic acid cycle forATP production, as well as building blocks such as lipids andnucleotides to sustain the cell proliferation. Gin metabolism in cancercells is regulated and cross-talks with multiple oncogenic pathways (GaoP, et al., “c-Myc Suppression of miR-23a/b Enhances MitochondrialGlutaminase Expression and Glutamine Metabolism”, Nature. 458(7239)(2009), pp. 762-5; Duran R V, et al. “Glutaminolysis ActivatesRag-mTORC1 Signaling”, Mol Cell. 47(3) (2012), pp. 349-58; Thangavelu K,et al., “Structural Basis for the Allosteric Inhibitory mechanism ofHuman Kidney-Type Glutaminase (KGA) and its Regulation by Raf-Mek-ErkSignaling in Cancer Cell Metabolism”, J. Proc Natl Acad Sci USA. 109(20)(2012), pp. 7705-10; Son J, et al., “Glutamine supports pancreaticcancer growth through a KRAS-regulated metabolic pathway”, 496(7443)Nature. (2013), pp. 101-5.). (GLS1) is an essential enzyme thatcatalyzes the first step in glutamine metabolism, leading to thegeneration of glutamate and ammonia. Glutamate is also the criticalsubstrate for glutathione synthesis, which plays important role in redoxhomeostasis. GLS1 is overexpressed across many tumor types, and mycup-regulates GLS1 protein level through transcriptional repression ofmiR-23a and miR-23b. Suppression of GLS1 with selective small moleculeinhibitors may be valuable to treat different types of cancers (Wise D.R., et al., “Glutamine Addiction: a New Therapeutic Target in Cancer”,Trends Biochem Sci. 35(8) 2010, pp. 427-33; Shukla K, et al., “Design,Synthesis, and Pharmacological Evaluation ofBis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES)Analogs as Glutaminase Inhibitors”, J Med Chem. 55(23) (2012), pp.10551-63.).

Thus, there is a need for compounds that inhibit GLS1.

SUMMARY OF THE INVENTION

Each of the embodiments described below can be combined with any otherembodiment described herein not inconsistent with the embodiment withwhich it is combined. The phrase “or a pharmaceutically acceptable saltthereof” is implicit in the description of all compounds describedherein; however, in one aspect of any of the embodiments herein, thecompound is in the form of a free base.

Embodiments described herein relate to a compound of formula (I)

wherein

A and D are independently 5 or 6-membered heteroaryl optionallysubstituted by one or two R⁷ groups;

L is —(C₄-C₁₀ cycloalkyl)- optionally substituted by one to threesubstituents selected from the group consisting of halogen, cyano, C₁-C₄alkyl, hydroxy, and C₁-C₄ alkoxy;

R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10a), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10b), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₄ alkyl,C₁-C₄ alkoxy or C₃-C₆ cycloalkyl;

each R⁷ is each independently hydrogen, halogen, cyano, C₁-C₂ alkyl,hydroxy, C₁-C₂ alkoxy, or —N(R¹¹)(R¹²), wherein the C₁-C₂ alkyl and theC₁-C₂ alkoxy are each independently optionally substituted by halogen orhydroxy;

R^(10a) and R^(10b) are each independently hydrogen, C₁-C₄ alkyl,—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₁-C₄ alkyl,the C₄-C₁₀ cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups;

each R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is independently hydrogen, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, or 3-6 membered heterocycloalkyl,wherein the C₁-C₄ alkyl, the C₃-C₆ cycloalkyl, and the 3-6 memberedheterocycloalkyl are each independently optionally substituted by one,two or three substituents selected from the group consisting of halogen,cyano, hydroxy, and methoxy;

w is 0, 1, 2 or 3;

x is 0 or 1;

y is 0 or 1, provided that at least one of x and y is 0; and

z is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A and D areindependently thiadiazolyl, pyridazinyl optionally substituted by one ortwo R⁷ groups, and 1,2,4-triazinyl optionally substituted by R⁷.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of A andD is

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein y is 0.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein D is

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A is pyridazinyloptionally substituted by one or two R⁷ groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A is

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein x is 0 and y is 0 or1.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein x is 1 and y is 0.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is C₁-C₄ alkyland R^(10b) is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ and R² eachindependently C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is hydrogen.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is 5-6 membered heteroaryl optionally substituted by one or two R¹⁵groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the aryl and theheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂-pyridinyl, wherein each pyridinyl isoptionally substituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), and R^(10b) is C₁-C₄alkyl, wherein the C₁-C₄ alkyl, the 4-6 membered heterocycloalkyl, theC₆-C₁₀ aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) areeach independently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl), wherein the C₆ aryl and the 5-6 membered heteroaryl inR^(10a) are each independently optionally substituted by one or twohalogen or C₁-C₄ alkyl groups, and R^(10b) is C₁-C₄ alkyl optionallysubstituted by C₁-C₆ alkoxy.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —(CH₂)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups and R^(10b) is C₁-C₄ alkyl optionally substituted by C₁-C₂alkoxy.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂CH₂—O—CH₃.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) are each independently optionallysubstituted by one, two or three halogen, cyano, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²), —(CH₂)_(w)—C(O)N(R¹¹)(R¹²),—C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or —S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —CH₂-(5-6membered heteroaryl) optionally substituted by one or two halogen orC₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R² is cyclopropyl.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein L is

x is 0 and y is 0.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) optionally substituted byone or two C₁-C₄ alkyl groups and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyrazolyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II)

wherein

A and D are independently

provided that at least one of A and D is

L is —(C₄-C₁₀ cycloalkyl)- optionally substituted by one to threesubstituents selected from the group consisting of halogen, cyano, C₁-C₄alkyl, hydroxy, and C₁-C₄ alkoxy;

R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10a), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10b), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen, halogen, C₁-C₄ alkyl,C₁-C₄ alkoxy or C₃-C₆ cycloalkyl;

R⁷, R⁸ and R⁹ are each independently hydrogen, halogen, cyano, C₁-C₂alkyl, hydroxy, C₁-C₂ alkoxy, or —N(R¹¹)(R¹²), wherein the C₁-C₂ alkyland the C₁-C₂ alkoxy are each independently optionally substituted byhalogen or hydroxy;

R^(10a) and R^(10b) are each independently hydrogen, C₁-C₄ alkyl,—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₁-C₄ alkyl,the C₄-C₁₀ cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups;

each R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is independently hydrogen, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, or 3-6 membered heterocycloalkyl,wherein the C₁-C₄ alkyl, the C₃-C₆ cycloalkyl, and the 3-6 memberedheterocycloalkyl are each independently optionally substituted by one,two or three substituents selected from the group consisting of halogen,cyano, hydroxy, and methoxy;

w is 0, 1, 2 or 3;

x is 0 or 1;

y is 0 or 1, provided that at least one of x and y is 0; and

z is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein y is 0.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein D is

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein A is

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein A is

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein x is 0 and y is 0 or1.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein x is 1 and y is 0.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is C₁-C₄ alkyland R^(10b) is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ and R² eachindependently C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is hydrogen.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is 5-6 membered heteroaryl optionally substituted by one or two R¹⁵groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the aryl and theheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂-pyridinyl, wherein each pyridinyl isoptionally substituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), and R^(10b) is C₁-C₄alkyl, wherein the C₁-C₄ alkyl, the 4-6 membered heterocycloalkyl, theC₆-C₁₀ aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) areeach independently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl), wherein the C₆ aryl and the 5-6 membered heteroaryl inR^(10a) are each independently optionally substituted by one or twohalogen or C₁-C₄ alkyl groups, and R^(10b) is C₁-C₄ alkyl optionallysubstituted by C₁-C₆ alkoxy.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —(CH₂)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups and R^(10b) is C₁-C₄ alkyl optionally substituted by C₁-C₂alkoxy.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂CH₂—O—CH₃.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) are each independently optionallysubstituted by one, two or three halogen, cyano, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²), —(CH₂)_(w)—C(O)N(R¹¹)(R¹²),—C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or —S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —CH₂-(5-6membered heteroaryl) optionally substituted by one or two halogen orC₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R² is cyclopropyl.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein L is

x is 0 and y is 0.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or R² is —C(O)R^(10b) and R¹ is hydrogen,C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10b), or 5-6 membered heteroaryl,wherein the C₃-C₆ cycloalkyl and the 5-6 membered heteroaryl areindependently optionally substituted by one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) optionally substituted byone or two C₁-C₄ alkyl groups and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyrazolyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein, wherein L is

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (II), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III)

wherein

A and D are independently

provided that at least one of A and D is

L is —(C₄-C₁₀ cycloalkyl)- optionally substituted by one to threesubstituents selected from the group consisting of halogen, cyano, C₁-C₄alkyl, hydroxy, and C₁-C₄ alkoxy;

R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10a), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10b), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R³ and R⁴ are each independently hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, or C₃-C₆ cycloalkyl;

R⁷, R⁸ and R⁹ are each independently hydrogen, halogen, cyano, C₁-C₂alkyl, hydroxy, C₁-C₂ alkoxy, or —N(R¹¹)(R¹²), wherein the C₁-C₂ alkyland the C₁-C₂ alkoxy are each independently optionally substituted byhalogen or hydroxy;

R^(10a) and R^(10b) are each independently hydrogen, C₁-C₄ alkyl,—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₁-C₄ alkyl,the C₄-C₁₀ cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups;

each R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is independently hydrogen, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, or 3-6 membered heterocycloalkyl,wherein the C₁-C₄ alkyl, the C₃-C₆ cycloalkyl, and the 3-6 memberedheterocycloalkyl are each independently optionally substituted by one,two or three substituents selected from the group consisting of halogen,cyano, hydroxy, and methoxy;

w is 0, 1, 2 or 3;

x is 0 or 1; and

z is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein D is

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein A is

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein A is

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein x is 0.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein x is 1.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is C₁-C₄ alkyland R^(10b) is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R¹ and R² eachindependently C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is hydrogen.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is 5-6 membered heteroaryl optionally substituted by one or two R¹⁵groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the aryl and theheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂-pyridinyl, wherein each pyridinyl isoptionally substituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), and R^(10b) is C₁-C₄alkyl, wherein the C₁-C₄ alkyl, the 4-6 membered heterocycloalkyl, theC₆-C₁₀ aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) areeach independently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl), wherein the C₆ aryl and the 5-6 membered heteroaryl inR^(10a) are each independently optionally substituted by one or twohalogen or C₁-C₄ alkyl groups, and R^(10b) is C₁-C₄ alkyl optionallysubstituted by C₁-C₆ alkoxy.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —(CH₂)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups and R^(10b) is C₁-C₄ alkyl optionally substituted by C₁-C₂alkoxy.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂CH₂—O—CH₃.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) are each independently optionallysubstituted by one, two or three halogen, cyano, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²), —(CH₂)_(w)—C(O)N(R¹¹)(R¹²),—C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or —S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —CH₂-(5-6membered heteroaryl) optionally substituted by one or two halogen orC₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R² is cyclopropyl.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein wherein L is

x is 0 and y is 0.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) optionally substituted byone or two C₁-C₄ alkyl groups and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyrazolyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein, wherein L is

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (III), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV)

wherein

A is

L is —(C₄-C₁₀ cycloalkyl)- optionally substituted by one to threesubstituents selected from the group consisting of halogen, cyano, C₁-C₄alkyl, hydroxy, and C₁-C₄ alkoxy;

R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10a), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10b), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R³ and R⁴ are each independently hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, or C₃-C₆ cycloalkyl;

R⁷, R⁸ and R⁹ are each independently hydrogen, halogen, cyano, C₁-C₂alkyl, hydroxy, C₁-C₂ alkoxy, or —N(R¹¹)(R¹²), wherein the C₁-C₂ alkyland the C₁-C₂ alkoxy are each independently optionally substituted byhalogen or hydroxy;

R^(10a) and R^(11b) are each independently hydrogen, C₁-C₄ alkyl,—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₁-C₄ alkyl,the C₄-C₁₀ cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups; each R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ isindependently hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, or3-6 membered heterocycloalkyl, wherein the C₁-C₄ alkyl, the C₃-C₆cycloalkyl, and the 3-6 membered heterocycloalkyl are each independentlyoptionally substituted by one, two or three substituents selected fromthe group consisting of halogen, cyano, hydroxy, and methoxy;

w is 0, 1, 2 or 3;

x is 0 or 1; and

z is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein A is

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein A is

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein x is 0.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein x is 1.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is C₁-C₄ alkyland R^(10b) is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R¹ and R² eachindependently C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is hydrogen.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is 5-6 membered heteroaryl optionally substituted by one or two R¹⁵groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the aryl and theheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂-pyridinyl, wherein each pyridinyl isoptionally substituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), and R^(10b) is C₁-C₄alkyl, wherein the C₁-C₄ alkyl, the 4-6 membered heterocycloalkyl, theC₆-C₁₀ aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) areeach independently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl), wherein the C₆ aryl and the 5-6 membered heteroaryl inR^(10a) are each independently optionally substituted by one or twohalogen or C₁-C₄ alkyl groups, and R^(10b) is C₁-C₄ alkyl optionallysubstituted by C₁-C₆ alkoxy.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —(CH₂)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups and R^(10b) is C₁-C₄ alkyl optionally substituted by C₁-C₂alkoxy.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂CH₂—O—CH₃.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) are each independently optionallysubstituted by one, two or three halogen, cyano, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²), —(CH₂)_(w)—C(O)N(R¹¹)(R¹²),—C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or —S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —CH₂-(5-6membered heteroaryl) optionally substituted by one or two halogen orC₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R² is cyclopropyl.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein L is

x is 0 and y is 0.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) optionally substituted byone or two C₁-C₄ alkyl groups and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyrazolyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or R² is —C(O)R^(10b) and R¹ is hydrogen,C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10b), or 5-6 membered heteroaryl,wherein the C₃-C₆ cycloalkyl and the 5-6 membered heteroaryl areindependently optionally substituted by one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IV), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa)

wherein

L is —(C₄-C₁₀ cycloalkyl)- optionally substituted by one to threesubstituents selected from the group consisting of halogen, cyano, C₁-C₄alkyl, hydroxy, and C₁-C₄ alkoxy;

R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10a), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10b), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R³ and R⁴ are each independently hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, or C₃-C₆ cycloalkyl;

R⁷ and R⁸ are each independently hydrogen, halogen, cyano, C₁-C₂ alkyl,hydroxy, C₁-C₂ alkoxy, or —N(R¹¹)(R¹²), wherein the C₁-C₂ alkyl and theC₁-C₂ alkoxy are each independently optionally substituted by halogen orhydroxy;

R^(10a) and R^(11b) are each independently hydrogen, C₁-C₄ alkyl,—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₁-C₄ alkyl,the C₄-C₁₀ cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups;

each R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is independently hydrogen, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, or 3-6 membered heterocycloalkyl,wherein the C₁-C₄ alkyl, the C₃-C₆ cycloalkyl, and the 3-6 memberedheterocycloalkyl are each independently optionally substituted by one,two or three substituents selected from the group consisting of halogen,cyano, hydroxy, and methoxy;

w is 0, 1, 2 or 3;

x is 0 or 1; and

z is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein x is 0.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein x is 1.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is C₁-C₄ alkyland R^(10b) is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 06 aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R¹ and R² eachindependently C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is hydrogen.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is 5-6 membered heteroaryl optionally substituted by one or two R¹⁵groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the aryl and theheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂-pyridinyl, wherein each pyridinyl isoptionally substituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), and R^(10b) is C₁-C₄alkyl, wherein the C₁-C₄ alkyl, the 4-6 membered heterocycloalkyl, theC₆-C₁₀ aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) areeach independently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl), wherein the C₆ aryl and the 5-6 membered heteroaryl inR^(10a) are each independently optionally substituted by one or twohalogen or C₁-C₄ alkyl groups, and R^(10b) is C₁-C₄ alkyl optionallysubstituted by C₁-C₆ alkoxy.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —(CH₂)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups and R^(10b) is C₁-C₄ alkyl optionally substituted by C₁-C₂alkoxy.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂CH₂—O—CH₃.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) are each independently optionallysubstituted by one, two or three halogen, cyano, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²), —(CH₂)_(w)—C(O)N(R¹¹)(R¹²),—C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or —S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —CH₂-(5-6membered heteroaryl) optionally substituted by one or two halogen orC₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R² is cyclopropyl.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) optionally substituted byone or two C₁-C₄ alkyl groups and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyrazolyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVa), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb)

wherein

L is —(C₄-C₁₀ cycloalkyl)- optionally substituted by one to threesubstituents selected from the group consisting of halogen, cyano, C₁-C₄alkyl, hydroxy, and C₁-C₄ alkoxy;

R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10a), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —C(O)R^(10b), or 5-6membered heteroaryl, wherein the C₃-C₆ cycloalkyl and the 5-6 memberedheteroaryl are independently optionally substituted by one or two R¹⁵groups;

R³ and R⁴ are each independently hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, or C₃-C₆ cycloalkyl;

R^(10a) and R^(11b) are each independently hydrogen, C₁-C₄ alkyl,—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₁-C₄ alkyl,the C₄-C₁₀ cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups;

each R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is independently hydrogen, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, or 3-6 membered heterocycloalkyl,wherein the C₁-C₄ alkyl, the C₃-C₆ cycloalkyl, and the 3-6 memberedheterocycloalkyl are each independently optionally substituted by one,two or three substituents selected from the group consisting of halogen,cyano, hydroxy, and methoxy;

w is 0, 1, 2 or 3;

x is 0 or 1; and

z is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein x is 0.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein x is 1.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein L is

optionally substituted by one to three substituents selected from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is C₁-C₄ alkyland R^(10b) is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R¹ and R² eachindependently C₁-C₄ alkyl.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is hydrogen.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein at least one of R¹ andR² is 5-6 membered heteroaryl optionally substituted by one or two R¹⁵groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the aryl and theheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂-pyridinyl, wherein each pyridinyl isoptionally substituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), and R^(10b) is C₁-C₄alkyl, wherein the C₁-C₄ alkyl, the 4-6 membered heterocycloalkyl, theC₆-C₁₀ aryl, and the 5-10 membered heteroaryl in R^(10a) and R^(10b) areeach independently optionally substituted by one, two or three halogen,cyano, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl), wherein the C₆ aryl and the 5-6 membered heteroaryl inR^(10a) are each independently optionally substituted by one or twohalogen or C₁-C₄ alkyl groups, and R^(10b) is C₁-C₄ alkyl optionallysubstituted by C₁-C₆ alkoxy.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —(CH₂)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups and R^(10b) is C₁-C₄ alkyl optionally substituted by C₁-C₂alkoxy.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl and R^(10b) is —CH₂CH₂—O—CH₃.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is C₃-C₆ cycloalkyl optionally substituted by one or two R¹⁵ groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]Z-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) are each independently optionallysubstituted by one, two or three halogen, cyano, C₁-C₆ alkyl, hydroxy,C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²), —(CH₂)_(w)—C(O)N(R¹¹)(R¹²),—C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or —S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is —CH₂-(5-6membered heteroaryl) optionally substituted by one or two halogen orC₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R² is cyclopropyl.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) optionally substituted byone or two C₁-C₄ alkyl groups and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)-(5-6membered heteroaryl) optionally substituted by one or two C₁-C₄ alkylgroups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyrazolyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyrazolyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein L is

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein

R¹ is —C(O)R^(10a) and R² is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R² is —C(O)R^(10b) and R¹ is hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,—C(O)R^(10b), or 5-6 membered heteroaryl, wherein the C₃-C₆ cycloalkyland the 5-6 membered heteroaryl are independently optionally substitutedby one or two R¹⁵ groups; or

R¹ is —C(O)R^(10a) and R² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)R^(10a) andR² is —C(O)R^(10b).

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)—(C₄-C₁₀ cycloalkyl), —[C(R¹³)(R¹⁴)]_(z)-(4-6 memberedheterocycloalkyl), —[C(R¹³)(R¹⁴)]_(z)—(C₆-C₁₀ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-10 membered heteroaryl), wherein the C₄-C₁₀cycloalkyl, the 4-6 membered heterocycloalkyl, the C₆-C₁₀ aryl, and the5-10 membered heteroaryl in R^(10a) and R^(10b) are each independentlyoptionally substituted by one, two or three halogen, cyano, C₁-C₆ alkyl,hydroxy, C₁-C₆ alkoxy, —(CH₂)_(w)—N(R¹¹)(R¹²),—(CH₂)_(w)—C(O)N(R¹¹)(R¹²), —C(O)OR¹¹, —N(R¹¹)C(O)R¹², —S(O)₂R¹¹, or—S(O)N(R¹¹)(R¹²) groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl) or —[C(R¹³)(R¹⁴)]_(z)-(5-6 memberedheteroaryl) and R^(10b) is —[C(R¹³)(R¹⁴)]_(z)—(C₆ aryl), or—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the C₆ aryl andthe 5-6 membered heteroaryl in R^(10a) and R^(10b) are eachindependently optionally substituted by one or two halogen or C₁-C₄alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl) and R^(10b) is—[C(R¹³)(R¹⁴)]_(z)-(5-6 membered heteroaryl), wherein the 5-6 memberedheteroaryl in R^(10a) and R^(10b) are each independently optionallysubstituted by one or two C₁-C₄ alkyl groups.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein each R¹³ and R¹⁴ ishydrogen and each z is 1.

Embodiments described herein relate to a compound of formula (IVb), or apharmaceutically acceptable salt thereof, wherein R^(10a) is—CH₂-pyridinyl optionally substituted by one or two C₁-C₄ alkyl groupsand R^(10b) is —CH₂-pyridinyl optionally substituted by one or two C₁-C₄alkyl groups.

In some embodiments, the compound is selected from:

-   (rac)-2-phenyl-N-{6-[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl)methyl]pyridazin-3-yl}acetamide;-   2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   (rac)-2-(pyridin-2-yl)-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   2-(pyridin-2-yl)-N-(5-{[(1    S,3R)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   N-[5-({(1R,3S)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   N-[5-({(1    S,3R)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   2-phenyl-N-(5-{[(1R,3S)-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   (rac)-2-phenyl-N-(5-{[(cis)-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   2-phenyl-N-(5-{[(1    S,3R)-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide;-   (+)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide;-   (−)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide;-   (+)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide;-   (−)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide;-   (+)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;-   (−)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;-   (+)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide;-   (−)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide;-   2-(pyridin-2-yl)-N-{5-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;-   2-(pyridin-2-yl)-N-{5-[(trans-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;-   (rac)-N-[5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;-   N,N′-(spiro[3.3]heptane-2,6-diyldipyridazine-6,3-diyl)bis[2-(pyridin-2-yl)acetamide];-   2-(pyridin-2-yl)-N-{5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;-   (rac)-N-(5-{[(cis)-3-{5-[(2,2-dimethylpropanoyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropanamide;-   (+)-N-(5-{[(cis)-3-{5-[(2,2-dimethylpropanoyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropanamide;-   (−)-N-(5-{[(cis)-3-{5-[(2,2-dimethylpropanoyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2,2-dimethylpropanamide;-   (rac)-2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)propanamide;-   (+)-2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)propanamide;-   (−)-2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)propanamide;-   (rac)-5-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-amine;-   5-{[(1R,3S)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-amine;-   5-{[(1    S,3R)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol-2-amine;-   (rac)-N-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide;-   (rac)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide;-   (+)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide;-   (−)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-2-yl)acetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrazin-2-yl)acetamide;-   (rac)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}benzamide;-   (rac)-N-[(cis)-5-({3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5-yl)acetamide;-   (+)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5-yl)acetamide;-   (−)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5-yl)acetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin-3-yl)acetamide;-   (+)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin-3-yl)acetamide;-   (−)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin-3-yl)acetamide;-   (rac)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;-   (+)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;-   (−)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;-   (+)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-5-yl)acetamide;-   (−)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-5-yl)acetamide;-   N,N′-{[-1,2,2-trimethylcyclopentane-1,3-diyl]di-1,3,4-thiadiazole-5,2-diyl}diacetamide;-   N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2-yl)acetamide];-   N-[5-({cis-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   N-[5-({trans-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   (+)-N-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)-2-phenylacetamide;-   (−)-N-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)-2-phenylacetamide;-   (rac)-N-[5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   (rac)-N-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide;-   (+)-N-{5-[(cis)-3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;-   (−)-N-{5-[(cis)-3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide;-   (rac)-2-(pyridin-2-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;-   (+)-2-(pyridin-2-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;-   (−)-2-(pyridin-2-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;-   N-{6-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]pyridazin-3-yl}propanamide;-   (+)-2-(pyridin-2-yl)-N-[6-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]acetamide;-   (−)-2-(pyridin-2-yl)-N-[6-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]acetamide;-   (rac)-2-methyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide;-   (+)-2-methyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide;-   (−)-2-methyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide;-   N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide;-   (+)-2-phenyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide;-   (−)-2-phenyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide;-   (rac)-2-(pyridin-2-yl)-N-[5-({(cis)-3-[5-(pyrimidin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   2-(pyridin-2-yl)-N-[5-({(cis)-3-[5-(pyrimidin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   2-(pyridin-2-yl)-N-[5-({3-[5-(trans)(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   2-(pyridin-2-yl)-N-[5-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   (rac)-N-[5-({(cis)-3-[5-(pyrazin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;-   (rac)-N-(5-{[(cis)-3-{5-[(1-methyl-1H-pyrazol-3-yl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide;-   N-(5-{[(cis)-3-{5-[(1-methyl-1H-pyrazol-3-yl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide;-   3-methoxy-N-{5-[(cis)-3-{[6-(propanoylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}propanamide;-   (+)-N-(6-{[(cis)-3-(5-{[(1-methyl-1H-pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)propanamide;-   (−)-N-(6-{[(cis)-3-(5-{[(1-methyl-1H-pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)propanamide;-   N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)diacetamide;-   (rac)-N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-methylpropanamide);-   (S)—N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2-methylpropanamide);-   (rac)-N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1-methyl-1H-pyrazol-3-yl)acetamide];-   (R)—N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1-methyl-1H-pyrazol-3-yl)acetamide];-   (S)—N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1-methyl-1H-pyrazol-3-yl)acetamide];-   N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2-yl)acetamide];-   N-[6-({cis-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2-phenylacetamide;-   N-[6-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide;-   (+)-2-(pyridin-2-yl)-N-{5-[(1-(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)ethyl]-1,3,4-thiadiazol-2-yl}acetamide;-   (−)-2-(pyridin-2-yl)-N-{5-[(1-(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)ethyl]-1,3,4-thiadiazol-2-yl}acetamide;-   2-methyl-N-{5-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}propanamide;-   N-{5-[cis-3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4-thiadiazol-2-yl}propanamide;-   N-{5-[trans-3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4-thiadiazol-2-yl}propanamide;-   N-[5-(cis-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclobutyl)-1,3,4-thiadiazol-2-yl]-2-(5-methylpyridin-2-yl)acetamide;-   2-(5-methylpyridin-2-yl)-N-(5-{[cis-3-(5-{[(5-methylpyridin-2-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   2-(5-methylpyridin-2-yl)-N-(5-{[trans-3-(5-{[(5-methylpyridin-2-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   N-[6-({(cis)-3-[5-(cyclopropylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide;-   2-(5-methylpyridin-2-yl)-N-{5-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;-   2-(5-methylpyridin-2-yl)-N-{5-[cis-3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4-thiadiazol-2-yl}acetamide;-   N-[6-({trans-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide;-   N-[5-(cis-3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclobutyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide;-   N-[6-({trans-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide;-   (+)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}pyridine-2-carboxamide;-   (−)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}pyridine-2-carboxamide;-   2-phenyl-N-{6-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]pyridazin-3-yl}acetamide;-   N-{5-[(1    S,3R)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propanamide;-   2-methyl-N-{5-[(1    S,3R)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propanamide;-   (+)-3-methoxy-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propanamide;-   (−)-3-methoxy-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propanamide;-   2-(pyridin-2-yl)-N-{5-[(trans-3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;-   2-(pyridin-2-yl)-N-{5-[(cis-3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide;-   2-methyl-N-{6-[cis-3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]pyridazin-3-yl}propanamide;-   (+)-2-(1-methyl-1H-pyrazol-3-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;-   (−)-2-(1-methyl-1H-pyrazol-3-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;-   2-(1-methyl-1H-imidazol-4-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide;-   (rac)-2-(pyridin-2-yl)-N-(6-{[(cis)-3-(5-{[(2R)-tetrahydrofuran-2-ylacetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)acetamide;-   (+)-2-(pyridin-2-yl)-N-(6-{[(cis)-3-(5-{[(2R)-tetrahydrofuran-2-ylacetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)acetamide;-   (−)-2-(pyridin-2-yl)-N-(6-{[(cis)-3-(5-{[(2R)-tetrahydrofuran-2-ylacetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)acetamide;-   N-[6-({cis-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2-phenylacetamide;-   2-(pyridin-2-yl)-N-[5-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide;-   (S)—N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)dipropanamide;-   2-methyl-N-[5-(6-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}spiro[3.3]hept-2-yl)-1,3,4-thiadiazol-2-yl]propanamide;-   2-methyl-N-{5-[6-(5-{[(1-methyl-1H-pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)spiro[3.3]hept-2-yl]-1,3,4-thiadiazol-2-yl}propanamide;-   (rac)-1-methyl-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-1H-pyrazole-3-carboxamide;-   N,N′-[cyclopentane-1,3-diyldi-1,3,4-thiadiazole-5,2-diyl]bis[2-(pyridin-2-yl)acetamide];-   N,N′-[cyclohexane-1,3-diyldi-1,3,4-thiadiazole-5,2-diyl]bis[2-(pyridin-2-yl)acetamide];-   N,N′-(cyclohexane-1,4-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2-yl)acetamide];-   N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)diacetamide;-   (rac)-2-(1H-pyrazol-1-yl)-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide;-   (rac)-3-(1H-pyrazol-1-yl)-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)propanamide;-   (rac)-2-fluoro-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)benzamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1,3-thiazol-4-yl)acetamide;-   (rac)-2-fluoro-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)benzamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1,3-thiazol-4-yl)acetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1-methyl-1H-pyrazol-3-yl)acetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]    cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1-methyl-1H-pyrazol-3-yl)acetamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]    cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-fluorobenzamide;-   (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(imidazo[1,2-a]pyridin-2-yl)acetamide;    and-   (rac)-1-methyl-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-1H-imidazole-4-carboxamide,

or a pharmaceutically acceptable salt thereof.

Embodiments relate to a pharmaceutical composition comprising a compoundof any of the embodiments of the compounds of formula (I), formula (II),formula (III), formula (IV), formula (IVa), or formula (IVb), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent.

Embodiments relate to a pharmaceutical composition comprising a compoundof any of the embodiments of the compounds of formula (I), formula (II),formula (III), formula (IV), formula (IVa), or formula (IVb), or apharmaceutically acceptable salt thereof, with an anti-tumor agent orwith radiation therapy, for the treatment of cancer.

Embodiments relate to a pharmaceutical composition comprising a compoundof any of the embodiments of the compounds of formula (I), formula (II),formula (III), formula (IV), formula (IVa), or formula (IVb), or apharmaceutically acceptable salt thereof, with an anti-tumor agent, forthe treatment of cancer.

Embodiments relate to a method of treating abnormal cell growth in amammal comprising administering to the mammal an amount of a compositionof any of the embodiments of the compounds of formula (I), formula (II),formula (III), formula (IV), formula (IVa), or formula (IVb), or apharmaceutically acceptable salt thereof, that is effective in treatingabnormal cell growth.

Embodiments relate to a method of treating abnormal cell growth in amammal comprising administering to the mammal an amount of a compound ofany of the embodiments of the compounds of formula (I), formula (II),formula (III), formula (IV), formula (IVa), or formula (IVb), or apharmaceutically acceptable salt thereof, that is effective in treatingabnormal cell growth.

Embodiments relate to the method of treating abnormal cell growth,wherein the abnormal cell growth is cancer.

Embodiments relate to the method of treating cancer, wherein the canceris selected from the group consisting of basal cell cancer,medulloblastoma cancer, liver cancer, rhabdomyosarcoma, lung cancer,bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system, primary central nervous systemlymphoma, spinal axis tumors, brain stem glioma and pituitary adenoma,or a combination of one or more of the foregoing cancers.

Embodiments relate to the method of treating lung cancer, wherein thecancer is selected from the group consisting of lung cancer, cancer ofthe head or neck, colon cancer, breast cancer, and ovarian cancer, or acombination of one or more of the foregoing cancers.

DETAILED DESCRIPTION OF THE INVENTION

The following abbreviations may be used herein: Ac (acetyl); AcOH(acetic acid); Ac2O (acetic anhydride); aq. (aqueous); ca. (about orapproximately); DCM (dichloromethane); DEA (diethylamine); DIPEA(N,N-diisopropylethylamine); DMA (dimethylacetamide); DMF(dimethylformamide); DMSO (dimethylsulphoxide); Et (ethyl); Et₃N(triethylamine); EtOH (ethanol); EtOAc (ethyl acetate); Et₂O (diethylether); Hal (halogen); HATU(2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate); H BTU(o-(benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate);HPLC (high-performance liquid chromatography); hr (hour or hours, asappropriate); IPA (isopropyl alcohol); LCMS (liquid chromatography-massspectrometry); L-Selectride (lithium tri-sec-butylborohydride); Me(methyl); MeOH (methanol); MeCN (acetonitrile); min (minute or minutes,as appropriate); N (normal); N/D (not determined) NMR (nuclear magneticresonance); Pd/C (palladium on carbon); Pd₂(dba)₃(tris(dibenzylideneacetone)dipalladium(0)); Pd(dppf)C₂([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Ph(phenyl); Rt (retention time); sec (second or seconds, as appropriate);SFC (supercritical fluid chromatography); Si-Thiol (silica1-propanethiol); T3P (propylphosphonic anhydride); TBME (tert-butylmethyl ether); t-BuOH (2-methyl-2-propanol, tert-butanol or tert-butylalcohol); THF (tetrahydrofuran); TLC (thin layer chromatography); TMSCl(trimethylsilyl chloride); Tris (tris(hydroxymethyl)aminomethane or2-Amino-2-hydroxymethyl-propane-1,3-diol); U (units); and v/v(volume/volume).

The term “halogen”, as used herein, refers to a fluorine, chlorine,bromine, or iodine atom or fluoro, chloro, bromo, or iodo. Additionally,the term “halogen” refers to F, Cl, Br, or I. The terms fluorine, fluoroand F, for example, are understood to be equivalent herein.

The term “alkyl”, as used herein, refers to saturated monovalenthydrocarbon radicals containing, in certain embodiments, from one tosix, from one to four or from one to three carbon atoms, having straightor branched moieties. The term “C₁-C₆ alkyl” refers to an alkyl radicalcontaining from one to six carbon atoms, having straight or branchedmoieties. The term “C₁-C₆ alkyl” includes within its definition theterms “C₁-C₂ alkyl”, “C₁-C₃ alkyl”, and “C₁-C₄ alkyl”. Examples of alkylgroups include, but are not limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl,3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, and thelike.

The term “alkoxy”, as used herein, refers to an alkyl radical that issingle bonded to an oxygen atom. The attachment point of an alkoxyradical to a molecule is through the oxygen atom. An alkoxy radical maybe depicted as alkyl-O—. The term “C₁-C₆ alkoxy”, refers to an alkoxyradical containing from one to six carbon atoms, having straight orbranched moieties. The terms “C₁-C₂ alkoxy” and “C₁-C₄ alkoxy”, refer toan alkoxy radical containing from one to two carbon atoms and from oneto four carbon atoms, respectively, having straight or branchedmoieties. Alkoxy groups, include, but are not limited to, methoxy,ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like.

The term “cycloalkyl”, as used herein, refers to a monocyclic, fused orbridged bicyclic or tricyclic carbocyclic ring group containing, incertain embodiments, from three to ten carbon atoms. As used herein, acycloalkyl group rings may optionally contain one or two double bonds.The term “cycloalkyl” also includes spirocyclic cycloalkyl groups,including multi-ring systems joined by a single atom. The terms “C₃-C₁₀cycloalkyl”, “C₃-C₇ cycloalkyl”, “C₃-C₄ cycloalkyl”, “C₃-C₆ cycloalkyl”,“C₄-C₁₀ cycloalkyl”, and “C₅-C₇ cycloalkyl” contain from three to ten,from three to seven, from three to four, from three to six, from four toten, and from five to seven carbon atoms, respectively. Cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[5.2.0]nonanyl,adamantanyl, spiro[3.3]heptanyl, and the like.

The term “heterocycloalkyl”, as used herein, refers to a non-aromatic,monocyclic, fused or bridged bicyclic or tricyclic or spirocyclic ringgroup containing, in certain embodiments, a total of three to ten ringatoms, in which one to four ring atoms are heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and wherein the sulfur atommay be optionally oxidized with one or two oxygen atoms, the remainingring atoms being carbon, with the proviso that such ring systems may notcontain two adjacent oxygen atoms or two adjacent sulfur atoms. Theheterocycloalkyl ring may also be substituted by an oxo (═O) group atany available carbon atom. The rings may also have one or more doublebonds. Furthermore, such groups may be bonded to the remainder of thecompounds of embodiments disclosed herein through either a carbon atomor a heteroatom, if possible. The terms “3-10 memberedheterocycloalkyl”, “4-10 membered heterocycloalkyl”, “3-7 memberedheterocycloalkyl”, “3-6 membered heterocycloalkyl”, and “4-6 memberedheterocycloalkyl” contain from three to ten, from four to ten, fromthree to seven, from three to six carbon atoms, and from four to sixcarbon atoms, respectively. Examples of saturated heterocycloalkylgroups include, but are not limited to:

Examples of suitable partially unsaturated heterocycloalkyl groupsinclude, but are not limited to:

The term “aryl”, as used herein, refers to a group derived from anaromatic hydrocarbon containing in certain embodiments, from six to tencarbon atoms. The term “C₆-C₁₀ aryl” contains from five to ten carbonatoms. Examples of such groups include, but are not limited to, phenyland naphthyl. The term “aryl” also includes fused polycyclic aromaticring systems in which an aromatic ring is fused to one or more rings.Examples include, but are not limited to, 1-naphthyl, 2-naphthyl,1-anthracyl and 2-anthracyl. Also included within the scope of the term“aryl”, as it is used herein, is a group in which an aromatic ring isfused to one or more non-aromatic rings, such as in an indanyl,phenanthridinyl, or tetrahydronaphthyl, where the radical or point ofattachment is on the aromatic ring.

The term “heteroaryl, as used herein, refers to an aromatic monocyclicor bicyclic heterocyclic group having a total of from 5 to 12 atoms inits ring, and containing from 2 to 9 carbon atoms and from one to fourheteroatoms each independently selected from nitrogen, oxygen, andsulfur, with the proviso that the ring of said group does not containtwo adjacent oxygen atoms or two adjacent sulfur atoms. The terms“5-membered heteroaryl”, “6-membered heteroaryl”, “5-10 memberedheteroaryl”, “5-12 membered heteroaryl”, “5-6 membered heteroaryl”, “4-6membered heteroaryl”, and “3-5 membered heteroaryl” contain five, six,from five to ten, from five to twelve, contain from five to six, fromfour to six ring atoms, and from three to five ring atoms, respectively.The heteroaryl groups include benzo-fused ring systems. Examples ofheteroaryl groups include, but are not limited to, pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl,triazolyl, oxadiazolyl, furazanyl, thiadiazolyl, thiazolyl, tetrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl,isoindolyl, indolizinyl, benzofuranyl, benzothiophenyl, indazolyl,benzimidazolyl, benzoxazolyl, furo[3,2-b]pyridinyl, benzothiazolyl,benzofurazanyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, cinnolinyl, phthalazinyl,pyrido[3,4-d]pyrimidinyl, pteridinyl, and the like.

Also included within the scope of the term “5-12 membered heteroaryl”,as used herein, are benzo-fused unsaturated nitrogen heterocycles, whichrefer to a heterocyclic group in which a heteroatomic ring is fused toone or more aromatic rings. Examples include, but are not limited to,indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,and the like.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

As used herein, an “effective” amount refers to an amount of asubstance, agent, compound, or composition that is of sufficientquantity to result in a decrease in severity of disease symptoms, anincrease in frequency and duration of disease symptom-free periods, or aprevention of impairment or disability due to the diseaseaffliction—either as a single dose or according to a multiple doseregimen, alone or in combination with other agents or substances. One ofordinary skill in the art would be able to determine such amounts basedon such factors as the subject's size, the severity of the subject'ssymptoms, and the particular composition or route of administrationselected. The subject may be a human or non-human mammal (e.g., rabbit,rat, mouse, monkey or other lower-order primate).

Embodiments disclosed herein include isotopically-labeled compounds,which are identical to those recited in formula (I), formula (II),formula (III), formula (IV), formula (IVa), or formula (IVb), but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the embodiments disclosed herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds described hereinand pharmaceutically acceptable salts of said compounds which containthe aforementioned isotopes and/or other isotopes of other atoms arewithin the scope of the present embodiments. Certainisotopically-labeled compounds of the embodiments disclosed herein, forexample, those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically-labeled compounds of embodiments disclosed herein cangenerally be prepared by carrying out the procedures disclosed in theSchemes and/or in the Examples and Preparations below, by substituting areadily available isotopically-labeled reagent for anon-isotopically-labeled reagent.

Some embodiments relate to the pharmaceutically acceptable salts of thecompounds described herein. Pharmaceutically acceptable salts of thecompounds described herein include the acid addition and base additionsalts thereof.

Some embodiments also relate to the pharmaceutically acceptable acidaddition salts of the compounds described herein. Suitable acid additionsalts are formed from acids which form non-toxic salts. Non-limitingexamples of suitable acid addition salts, i.e., salts containingpharmacologically acceptable anions, include, but are not limited to,the acetate, acid citrate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, bitartrate, borate,camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate,formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methanesulfonate, methylsulphate,naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate,palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,pyroglutamate, saccharate, stearate, succinate, tannate, tartrate,p-toluenesulfonate, tosylate, trifluoroacetate and xinofoate salts.

Additional embodiments relate to base addition salts of the compoundsdescribed herein. Suitable base addition salts are formed from baseswhich form non-toxic salts. Non-limiting examples of suitable base saltsinclude the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

The compounds described herein that are basic in nature are capable offorming a wide variety of salts with various inorganic and organicacids. The acids that may be used to prepare pharmaceutically acceptableacid addition salts of such basic compounds described herein are thosethat form non-toxic acid addition salts, e.g., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compoundsdescribed herein that include a basic moiety, such as an amino group,may form pharmaceutically acceptable salts with various amino acids, inaddition to the acids mentioned above.

The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of thecompounds described herein that are acidic in nature are those that formnon-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (e.g.,potassium and sodium) and alkaline earth metal cations (e.g., calciumand magnesium), ammonium or water-soluble amine addition salts such asN-methylglucamine-(meglumine), and the lower alkanolammonium and otherbase salts of pharmaceutically acceptable organic amines.

The compounds of the embodiments described herein include allstereoisomers (e.g., cis and trans isomers) and all optical isomers ofcompounds described herein (e.g., R and S enantiomers), as well asracemic, diastereomeric and other mixtures of such isomers. While allstereoisomers are encompassed within the scope of our claims, oneskilled in the art will recognize that particular stereoisomers may bepreferred.

In some embodiments, the compounds described herein can exist in severaltautomeric forms, including the enol and imine form, and the keto andenamine form and geometric isomers and mixtures thereof. All suchtautomeric forms are included within the scope of the presentembodiments. Tautomers exist as mixtures of a tautomeric set insolution. In solid form, usually one tautomer predominates. Even thoughone tautomer may be described, the present embodiments includes alltautomers of the present compounds.

The present embodiments also include atropisomers of the compoundsdescribed herein. Atropisomers refer to compounds that can be separatedinto rotationally restricted isomers.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).Methods for making pharmaceutically acceptable salts of compoundsdescribed herein are known to one of skill in the art.

The term “solvate” is used herein to describe a molecular complexcomprising a compound described herein and one or more pharmaceuticallyacceptable solvent molecules, for example, ethanol.

The compounds described herein may also exist in unsolvated and solvatedforms. Accordingly, some embodiments relate to the hydrates and solvatesof the compounds described herein.

Compounds described herein containing one or more asymmetric carbonatoms can exist as two or more stereoisomers. Where a compound describedherein contains an alkenyl or alkenylene group, geometric cis/trans (orZ/E) isomers are possible. Where structural isomers are interconvertiblevia a low energy barrier, tautomeric isomerism (‘tautomerism’) canoccur. This can take the form of proton tautomerism in compoundsdescribed herein containing, for example, an imino, keto, or oximegroup, or so-called valence tautomerism in compounds which contain anaromatic moiety. A single compound may exhibit more than one type ofisomerism.

Included within the scope of the present embodiments are allstereoisomers, geometric isomers and tautomeric forms of the compoundsdescribed herein, including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or I-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC) or SFC.

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where a compound described herein contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (3) anytumors that proliferate by receptor tyrosine kinases; (4) any tumorsthat proliferate by aberrant serine/threonine kinase activation; (5)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs; (6) any tumors thatproliferate by aberrant signaling, metabolic, epigenetic andtranscriptional mechanism; and (7) benign and malignant cells of otherproliferative diseases in which aberrant signaling, metabolic,epigenetic and transcriptional mechanism.

Further embodiments relate to methods of treating abnormal cell growthin a mammal. Additional embodiments relate to a method of treatingabnormal cell growth in a mammal comprising administering to the mammalan amount of a compound described herein that is effective in treatingabnormal cell growth.

In other embodiments, the abnormal cell growth is cancer.

In some embodiments, the cancer is selected from the group consisting oflung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer,cancer of the head or neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, rectal cancer, cancer of the anal region,stomach cancer, hepatic carcinoma, colon cancer, breast cancer, uterinecancer, carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, prostatecancer, hematology malignancy, chronic or acute leukemia, lymphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter, renalcell carcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors,glioblastoma, brain stem glioma, pituitary adenoma, or a combination oftwo or more of the foregoing cancers.

Additional embodiments relate to methods of treating cancer solid tumorsin a mammal. Some embodiments relate to the treatment of cancer solidtumor in a mammal comprising administering to the mammal an amount of acompound described herein that is effective in treating said cancersolid tumor.

In other embodiments, the cancer solid tumor is breast, lung, colon,brain, prostate, stomach, pancreatic, ovarian, skin (melanoma),endocrine, uterine, testicular, or bladder.

Further embodiments relate to methods of treating abnormal cell growthin a mammal which comprises administering to said mammal an amount of acompound described herein that is effective in treating abnormal cellgrowth in combination with an anti-tumor agent selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, radiation, cellcycle inhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

More embodiments relate to pharmaceutical compositions for treatingabnormal cell growth in a mammal comprising an amount of a compounddescribed herein that is effective in treating abnormal cell growth, anda pharmaceutically acceptable carrier.

Additional embodiments relate to a method of treating abnormal cellgrowth in a mammal, including a human, comprising administering to themammal an amount of a compound described herein, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, that is effectivein treating abnormal cell growth. In one embodiment of this method, theabnormal cell growth is cancer, including, but not limited to, lungcancer, bone cancer, pancreatic cancer, skin cancer, cancer of the heador neck, cutaneous or intraocular melanoma, uterine cancer, ovariancancer, rectal cancer, cancer of the anal region, stomach cancer, coloncancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In one embodimentthe method comprises comprising administering to a mammal an amount of acompound described herein that is effective in treating said cancersolid tumor. In one preferred embodiment the solid tumor is breast,lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin(melanoma), endocrine, uterine, testicular, and bladder cancer.

In another embodiment of said method, said abnormal cell growth is abenign proliferative disease, including, but not limited to, psoriasis,benign prostatic hypertrophy or restinosis.

Some embodiments relate to a method of treating abnormal cell growth ina mammal which comprises administering to said mammal an amount of acompound described herein, or a pharmaceutically acceptable salt,solvate, hydrate or prodrug thereof, that is effective in treatingabnormal cell growth in combination with an anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

Additional embodiments relate to a pharmaceutical composition fortreating abnormal cell growth in a mammal, including a human, comprisingan amount of a compound described herein, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, that is effectivein treating abnormal cell growth, and a pharmaceutically acceptablecarrier. In one embodiment of said composition, said abnormal cellgrowth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

Further embodiments relate to a method of treating abnormal cell growthin a mammal which comprises administering to said mammal an amount of acompound described herein, or a pharmaceutically acceptable salt,solvate, or hydrate thereof, that is effective in treating abnormal cellgrowth in combination with another anti-tumor agent selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens. Some embodiments contemplate a pharmaceuticalcomposition for treating abnormal cell growth wherein the compositionincludes a compound described herein, or a pharmaceutically acceptablesalt, solvate, or hydrate thereof, that is effective in treatingabnormal cell growth, and another anti-tumor agent selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

Yet more embodiments relate to a method of treating a disorderassociated with angiogenesis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound described herein,as defined above, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof, that is effective in treating said disorderin combination with one or more anti-tumor agents listed above. Suchdisorders include cancerous tumors such as melanoma; ocular disorderssuch as age-related macular degeneration, presumed ocular histoplasmosissyndrome, and retinal neovascularization from proliferative diabeticretinopathy; rheumatoid arthritis; bone loss disorders such asosteoporosis, Paget's disease, humoral hypercalcemia of malignancy,hypercalcemia from tumors metastatic to bone, and osteoporosis inducedby glucocorticoid treatment; coronary restenosis; and certain microbialinfections including those associated with microbial pathogens selectedfrom adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp.,Bordetella pertussis, and group A Streptococcus.

Some embodiments relate to a method of (and to a pharmaceuticalcomposition for) treating abnormal cell growth in a mammal whichcomprise an amount of a compound described herein, or a pharmaceuticallyacceptable salt, solvate, or hydrate thereof, in combination with anamount of one or more substances selected from anti-angiogenesis agents,signal transduction inhibitors inhibitor (e.g., inhibiting the means bywhich regulatory molecules that govern the fundamental processes of cellgrowth, differentiation, and survival communicated within the cell), andantiproliferative agents, which amounts are together effective intreating said abnormal cell growth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound described herein in the methods and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), andArcoxia (etoricoxib). Examples of useful matrix metalloproteinaseinhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO96/27583 (published Mar. 7, 1996), European Patent Application No.97304971.1 (filed Jul. 8, 1997), European Patent Application No.99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998),WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13,1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (publishedAug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European PatentPublication 606,046 (published Jul. 13, 1994), European PatentPublication 931,788 (published Jul. 28, 1999), WO 90/05719 (publishedMay 331, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCTInternational Application No. PCT/IB98/01113 (filed Jul. 21, 1998),European Patent Application No. 99302232.1 (filed Mar. 25, 1999), GreatBritain patent application number 9912961.1 (filed Jun. 3, 1999), U.S.Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat.No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issuedJan. 19, 1999), and European Patent Publication 780,386 (published Jun.25, 1997), all of which are herein incorporated by reference in theirentirety. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in combination with thecompounds described herein are AG-3340, RO 32-3555, RS 13-0830, and thefollowing compounds:

-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic    acid;-   3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   (2R, 3R)    1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic    acid;-   4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic    acid hydroxyamide;-   (2R, 3R)    1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic    acid;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic    acid;-   3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide; and-   3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic    acid hydroxyamide;

and pharmaceutically acceptable salts and solvates of said compounds.

VEGF inhibitors, for example, sutent and axitinib, can also be combinedwith a compound described herein. VEGF inhibitors are described in, forexample in WO 99/24440 (published May 20, 1999), PCT InternationalApplication PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613(published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S.Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356 (published Nov.12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No.5,886,020 (issued Mar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug.11, 1998), U.S. Pat. No. 6,653,308 (issued Nov. 25, 2003), WO 99/10349(published Mar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO97/22596 (published Jun. 26, 1997), WO 98/54093 (published Dec. 3,1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (publishedApr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), all of whichare herein incorporated by reference in their entirety. Other examplesof some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland,Wash., USA); Avastin, an anti-VEGF monoclonal antibody of Genentech,Inc. of South San Francisco, Calif.; and angiozyme, a synthetic ribozymefrom Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), andthe monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), may be administered incombination with a compound described herein. Such erbB2 inhibitorsinclude Herceptin, 2C₄, and pertuzumab. Such erbB2 inhibitors includethose described in WO 98/02434 (published Jan. 22, 1998), WO 99/35146(published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17,1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458(issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2,1999), each of which is herein incorporated by reference in itsentirety. ErbB2 receptor inhibitors useful in the embodiments describedherein are also described in U.S. Provisional Application No.60/117,341, filed Jan. 27, 1999, and in U.S. Provisional Application No.60/117,346, filed Jan. 27, 1999, both of which are herein incorporatedby reference in their entirety. Other erbb2 receptor inhibitors includeTAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome).

Various other compounds, such as styrene derivatives, have also beenshown to possess tyrosine kinase inhibitory properties, and some oftyrosine kinase inhibitors have been identified as erbB2 receptorinhibitors. More recently, five European patent publications, namely EP0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1 (published Jun.22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1(published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30,1992), refer to certain bicyclic derivatives, in particular quinazolinederivatives, as possessing anti-cancer properties that result from theirtyrosine kinase inhibitory properties. Also, World Patent Application WO92/20642 (published Nov. 26, 1992), refers to certain bis-mono andbicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitorsthat are useful in inhibiting abnormal cell proliferation. World PatentApplications WO96/16960 (published Jun. 6, 1996), WO 96/09294 (publishedMar. 6, 1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434(published Jan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO98/02438 (published Jan. 22, 1998), also refer to substituted bicyclicheteroaromatic derivatives as tyrosine kinase inhibitors that are usefulfor the same purpose. Other patent applications that refer toanti-cancer compounds are World Patent Application WO00/44728 (publishedAug. 3, 2000), EP 1029853A1 (published Aug. 23, 2000), and WO01/98277(published Dec. 12, 2001) all of which are incorporated herein byreference in their entirety.

Epidermal growth factor receptor (EGFR) inhibitors may be administeredin combination with a compound of the presentation invention. Such EGFRinhibitors include gefinitib, erlotinib, icotinib, afatinib anddacomitinib. Monoclonal antibody inhibitors of EGFR, such as cetuximab,may also be combined with a compound of the present invention.

PI3K inhibitors, such as PI3K beta inhibitors, may be administered incombination with a compound of the presentation invention.

Mammalian target of rapamycin (mTOR) inhibitors may be administered incombination with a compound of the presentation invention. Such mTORinhibitors include rapamycin analogs and ATP competitive inhibitors.

c-Met inhibitors may be administered in combination with a compound ofthe presentation invention. Such c-Met inhibitors include crizotinib andARQ-197. Monoclonal antibody inhibitors of c-Met, such as METMab, mayalso be combined with a compound of the present invention.

CDK inhibitors may be administered in combination with a compound of thepresentation invention. Such CDK inhibitors include palbociclib.

MEK inhibitors may be administered in combination with a compound of thepresentation invention. Such MEK inhibitors include PD-325901.

PARP inhibitors may be administered in combination with a compound ofthe presentation invention.

JAK inhibitors may be administered in combination with a compound of thepresentation invention.

An antagonist of a Programmed Death 1 protein (PD-1) may be administeredin combination with a compound of the presentation invention.

Other antiproliferative agents that may be used with the compoundsdescribed herein include inhibitors of the enzyme farnesyl proteintransferase and inhibitors of the receptor tyrosine kinase PDGFr,including the compounds disclosed and claimed in the following U.S.patent application Ser. No. 09/221,946 (filed Dec. 28, 1998); Ser. No.09/454,058 (filed Dec. 2, 1999); Ser. No. 09/501,163 (filed Feb. 9,2000); Ser. No. 09/539,930 (filed Mar. 31, 2000); Ser. No. 09/202,796(filed May 22, 1997); Ser. No. 09/384,339 (filed Aug. 26, 1999); andSer. No. 09/383,755 (filed Aug. 26, 1999); and the compounds disclosedand claimed in the following U.S. provisional patent applications:60/168,207 (filed Nov. 30, 1999); 60/170,119 (filed Dec. 10, 1999);60/177,718 (filed Jan. 21, 2000); 60/168,217 (filed Nov. 30, 1999), and60/200,834 (filed May 1, 2000). Each of the foregoing patentapplications and provisional patent applications is herein incorporatedby reference in their entirety.

A compound described herein may also be used with other agents useful intreating abnormal cell growth or cancer, including, but not limited to,agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocyte antigen 4) antibodies, and other agents capable ofblocking CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the farnesyl proteintransferase inhibitors described in the references cited in the“Background” section, supra. Specific CTLA4 antibodies that can be usedin the present embodiments include those described in U.S. ProvisionalApplication 60/113,647 (filed Dec. 23, 1998) which is hereinincorporated by reference in its entirety.

A compound described herein may be applied as a sole therapy or mayinvolve one or more other anti-tumor substances, for example thoseselected from, for example, mitotic inhibitors, for example vinblastine;alkylating agents, for example cis-platin, oxaliplatin, carboplatin andcyclophosphamide; anti-metabolites, for example 5-fluorouracil,capecitabine, cytosine arabinoside and hydroxyurea, or, for example, oneof the preferred anti-metabolites disclosed in European PatentApplication No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex (tamoxifen) or, for example anti-androgens such as Casodex(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).

The compounds described herein may be used alone or in combination withone or more of a variety of anti-cancer agents or supportive careagents. For example, the compounds described herein may be used withcytotoxic agents, e.g., one or more selected from the group consistingof a camptothecin, irinotecan HCl (Camptosar), edotecarin, SU-11248,epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, rituximab(Rituxan) bevacizumab (Avastin), imatinib mesylate (Gleevac), Erbitux,gefitinib (Iressa), and combinations thereof. Some embodiments alsocontemplate the use of the compounds described herein together withhormonal therapy, e.g., exemestane (Aromasin), Lupron, anastrozole(Arimidex), tamoxifen citrate (Nolvadex), Trelstar, and combinationsthereof. Further, some embodiments provide a compound described hereinalone or in combination with one or more supportive care products, e.g.,a product selected from the group consisting of Filgrastim (Neupogen),ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinationsthereof. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof the treatment.

The compounds described herein may be used with antitumor agents,alkylating agents, antimetabolites, antibiotics, plant-derived antitumoragents, camptothecin derivatives, tyrosine kinase inhibitors,antibodies, interferons, and/or biological response modifiers. In thisregard, the following is a non-limiting list of examples of secondaryagents that may be used with the compounds described herein.

Alkylating agents include, but are not limited to, nitrogen mustardN-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan,mitobronitol, carboquone, thiotepa, ranimustine, nimustine,temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin,bendamustine, carmustine, estramustine, fotemustine, glufosfamide,ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinatedalkylating compounds include but are not limited to, cisplatin,carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin orsatrplatin.

Antimetabolites include but are not limited to, methotrexate,6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) aloneor in combination with leucovorin, tegafur, UFT, doxifluridine,carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1,gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine,clofarabine, decitabine, eflornithine, ethynylcytidine, cytosinearabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed,ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed,triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or forexample, one of the preferred anti-metabolites disclosed in EuropeanPatent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid.

Antibiotics include but are not limited to: aclarubicin, actinomycin D,amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin,elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C,nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin,stimalamer, streptozocin, valrubicin or zinostatin.

Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron,anastrozole (Arimidex), doxercalciferol, fadrozole, formestane,anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant,Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), oranti-androgens such as bicalutamide, flutamide, mifepristone,nilutamide, Casodex®(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide)and combinations thereof.

Plant derived anti-tumor substances include for example those selectedfrom mitotic inhibitors, for example vinblastine, docetaxel (Taxotere)and paclitaxel.

Cytotoxic topoisomerase inhibiting agents include one or more agentsselected from the group consisting of aclarubicn, amonafide, belotecan,camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan,irinotecan HCl (Camptosar), edotecarin, epirubicin (Ellence), etoposide,exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone,rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, andcombinations thereof.

Immunologicals include interferons and numerous other immune enhancingagents. Interferons include interferon alpha, interferon alpha-2a,interferon, alpha-2b, interferon beta, interferon gamma-1a or interferongamma-n1. Other agents include PF3512676, filgrastim, lentinan,sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002,dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab,imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa),molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin,thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab,oregovomab, pemtumomab, Provenge.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth,or differentiation of tissue cells to direct them to have anti-tumoractivity. Such agents include krestin, lentinan, sizofiran, picibanil,or ubenimex.

Other anticancer agents include alitretinoin, ampligen, atrasentanbexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride,fotemustine, ibandronic acid, miltefosine, mitoxantrone, I-asparaginase,procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,tazarotne, TLK-286, Velcade, Tarceva, or tretinoin.

Other anti-angiogenic compounds include acitretin, fenretinide,thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide,combretastatin A-4, endostatin, halofuginone, rebimastat, removab,Revlimid, squalamine, ukrain and Vitaxin.

Platinum-coordinated compounds include but are not limited to,cisplatin, carboplatin, nedaplatin, or oxaliplatin.

Camptothecin derivatives include but are not limited to camptothecin,10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38,edotecarin, and topotecan.

Tyrosine kinase inhibitors include, for example, Iressa and SU5416.

Antibodies include, for example, Herceptin, Erbitux, Avastin, andRituximab.

Interferons include, for example, interferon alpha, interferon alpha-2a,interferon, alpha-2b, interferon beta, interferon gamma-1a andinterferon gamma-n1.

Biological response modifiers include agents that modify defensemechanisms of living organisms or biological responses, such assurvival, growth, or differentiation of tissue cells to direct them tohave anti-tumor activity. Such agents include, for example, krestin,lentinan, sizofiran, picibanil, and ubenimex.

Other antitumor agents include, for example, mitoxantrone,I-asparaginase, procarbazine, dacarbazine, hydroxycarbamide,pentostatin, and tretinoin. Additionally, PI3K inhibitors andRAS-targeted cancer treatments may be combined with the compoundsdescribed herein.

Some embodiments also relate to a pharmaceutical composition comprisinga compound of formula (I), formula (II), formula (III), formula (IV),formula (IVa), or formula (IVb), or a pharmaceutically acceptable saltor solvate thereof, as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

Further embodiments relate to a pharmaceutical composition whichcomprises mixing a compound of formula (I), formula (II), formula (III),formula (IV), formula (IVa), or formula (IVb), or a pharmaceuticallyacceptable salt or solvate thereof, as hereinbefore defined with apharmaceutically acceptable adjuvant, diluent or carrier.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound formula (I), formula (II), formula (III), formula (IV),formula (IVa), or formula (IVb), or pharmaceutically acceptable saltthereof, may be in the range from 1 mg to 1 gram, preferably 1 mg to 250mg, more preferably 10 mg to 100 mg.

The present embodiments also encompass sustained release compositions.

Administration of the compounds described herein (hereinafter the“active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumor substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex® (tamoxifen) or, for example anti-androgens such as Casodex®(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound described herein as an active ingredient. In addition, it mayinclude other medicinal or pharmaceutical agents, carriers, adjuvants,etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

The examples and preparations provided below further illustrate andexemplify the compounds described herein and methods of preparing suchcompounds. The scope of the embodiments described herein is not limitedin any way by the following examples and preparations. In the followingexamples, molecules with a single chiral center, unless otherwise noted,exist as a racemic mixture. Those molecules with two or more chiralcenters, unless otherwise noted, exist as a racemic mixture ofdiastereomers. Single enantiomers/diastereomers may be obtained bymethods known to those skilled in the art.

In the examples shown, salt forms were occasionally isolated as aconsequence of the mobile phase additives during HPLC basedchromatographic purification. In these cases, salts such as formate,trifluorooacetate and acetate were isolated and tested without furtherprocessing. It will be recognized that one of ordinary skill in the artwill be able to realize the free base form by standard methodology (suchas using ion exchange columns, or performing simple basic extractionsusing a mild aqueous base).

In general, the compounds described herein may be prepared by processesknown in the chemical arts, particularly in light of the descriptioncontained herein. Certain processes for the manufacture of the compoundsdescribed herein are provided as further features of the embodiments andare illustrated in the reaction schemes provided below and in theexperimental section.

Unless stated otherwise, the variables in Schemes A-H have the samemeanings as defined herein.

As exemplified in Scheme A, the mono-ester mono-acid A-1, which may beobtained either from commercial sources, or from selective esterhydrolysis or desymmetrization of symmetrical anhydrides under standardliterature conditions (see for example, J. Am. Chem. Soc., 2000, 122,9542 and Helv. Chim. Acta., 1983, 66, 2501), is subjected to selectivereduction of the carboxylic acid moiety using a reducing agent such asborane.dimethylsulfide to afford A-2. The alcohol in A-2 may behalogenated to form an alkyl halide such as an iodide or a bromide usingreagents such as iodine/triphenylphosphine in the presence of a basesuch as imidazole or carbon tetrabromide to afford A-3. The couplingpartner A-5 is obtained from the acylation of a commercially available2-amino-6-halogenated heterocycle, A-4, using an acid in the presence ofa standard coupling reagent such as HATU or HBTU in the presence of abase such as Hunig's base or triethylamine. The reaction between A-5 andA-3 takes place through a palladium-mediated process such as a Negishireaction. For example, the halogenated compound A-3 may be activated asan organometallic species such as an organozincate by treatment withspecies such as zinc dust in the presence of an activating agent such a1,2-dibromoethane and TMSCl in a solvent such as DMF, or withoutactivation by using diethyl zinc for the metallation process. Thezincate obtained may be coupled with the halogenated heterocycle A-5through a Negishi reaction using a palladium catalyst such as Pd₂(dba)₃in the presence of a suitable ligand such as tri(o-tolylphoshine) in asolvent such as DMF to afford A-6. The ester in A-6 is hydrolyzed by aninorganic base such as lithium hydroxide or sodium hydroxide in asolvent such as methanol and water to afford the carboxylic acid A-7.Condensation of A-7 with thiosemicarbazide in the presence of phosphorusoxychloride as both an activating and dehydrating agent provides theaminothiadiazole A-8. Acylation of A-8 either using by reaction with anacid chloride or by using a suitable amide coupling agent (such as T3P,HATU or HBTU) and an appropriate carboxylic acid in the presence of abase such as pyridine, TEA or Hunig's base in a solvent such as DMF orDMA affords A-9. Separation of the enantiomers may be carried out understandard methods known in the art such as chiral SFC or HPLC to affordthe single enantiomer A-9.

As exemplified in Scheme B, the di-acid B-1 may be either obtained fromcommercial sources, or prepared by methods, which are established in theliterature or reported herein. Condensation of B-1 withthiosemicarbazide in the presence of phosphorus oxychloride as both anactivating and dehydrating agent provides the bis-aminothiadiazole B-2.Acylation of B-2 either by reaction with an acid chloride or by using asuitable amide coupling agent (such as T3P, HATU or HBTU) and anappropriate carboxylic acid in the presence of a base such as pyridine,TEA or Hunig's base in a solvent such as DMF or DMA affords thesymmetrically substituted bis-aminothidiazole, B-3. Separation of theenantiomers may be carried out under standard methods known in the artsuch as chiral SFC or HPLC to afford single enantiomers of B-3.

As exemplified in Scheme C, the mono-ester mono-acid (A-1 in scheme A)is converted into the mono-thiadiazole under standard conditions knownin the art such as condensation with thiosemicarbazide in the presenceof an activating/dehydrating agent such as phosphorus oxychloride toprovide C-1. Acylation of C-1 is carried out under standard conditionssuch as condensation with acetyl chloride or acetic anhydride in thepresence of a base such as triethylamine in a solvent such as DMF toafford C-2. Ester hydrolysis of C-2 is carried out under basicconditions using a base such as NaOH or LiOH in a solvent such asmethanol to afford C-3. Condensation of C-3 with hydrazine in thepresence of a suitable coupling agent (such as T3P, HBTU or HATU) and abase (such as pyridine, TEA or DIPEA) in a suitable solvent such as DMFaffords C-4. Reaction with C-4 with an isothiocyanate in a suitablesolvent such as ethyl acetate, THF or methylene chloride affords C-5.Isothiocyanates are either commercially available or may be prepared bydirect reaction of an acid chloride with sodium isothiocyanate underconditions, which are well established in the literature. C-5 iscyclized by dehydration under acidic conditions in the presence of asuitable acid such as sulfuric acid to afford C-8. Alternatively, C-3 iscondensed with thiosemicarbazide in the presence of a suitable couplingagent (such as HBTU or HATU) and a base (such as TEA or DIPEA) in asuitable solvent such as DMF to afford C-6. C-6 is cyclized bydehydration under acidic conditions in the presence of a suitable acidsuch as sulfuric acid to afford C-7. Acylation of C-7 either using byreaction with an acid chloride or by using a suitable amide couplingagent (such as T3P, HATU or HBTU) and an appropriate carboxylic acid inthe presence of a base such as pyridine, TEA or Hunig's base in asolvent such as DMF or DMA affords C-8. Separation of the enantiomersmay be carried out under standard methods known in the art such aschiral SFC or HPLC to afford single enantiomer C-8.

As exemplified in Scheme D, the mono-ester mono-acid (A-s in Scheme A)is converted into the mono-thiadiazole under standard conditions knownin the art such as condensation with thiosemicarbazide in the presenceof an activating/dehydrating agent such as phosphorus oxychloride toprovide D-1. Acylation of D-1 either by reaction with an acid chlorideor by using a suitable amide coupling agent (such as T3P, HATU or HBTU)and an appropriate carboxylic acid in the presence of a base such aspyridine, TEA or Hunig's base in a solvent such as DMF or DMA affordsD-2. Ester hydrolysis of D-2 is carried out under basic conditions usinga base such as NaOH or LiOH in a solvent such as methanol to afford D-3.D-3 is condensed with thiosemicarbazide in the presence of a suitablecoupling agent (such as T3P, HBTU or HATU) and a base (such as pyridine,TEA or Hunig's base) in a suitable solvent such as DMF to afford D-4.D-4 is cyclized by dehydration under acidic conditions in the presenceof a suitable acid such as sulfuric acid to afford D-5. Acylation of D-5is carried out under standard conditions using an acylation agent suchas acetic anhydride in a solvent such as acetic acid to afford D-6.Separation of the enantiomers may be carried out under standard methodsknown in the art such as chiral SFC or HPLC to afford single enantiomerD-6.

As exemplified in Scheme E, the cyclic keto-acid E-1 may be eitherobtained from commercial sources, or prepared by methods, which areestablished in the literature or reported herein. Reaction of the ketonefunction with an organophosphorane in the presence of a base such assodium hydride in a solvent such as THF in a Horner-Wittig-Emmonsreaction gives the unsaturated ester, E-2. Reduction of the olefin underhydrogen pressure in the presence of a heterogeneous catalyst such aspalladium on carbon or platinum oxide in a solvent such as methanol ordichloromethane gives E-3 as a mixture of diastereomers in whichreduction from the less hindered face will be preferred. Condensation ofE-3 with thiosemicarbazide in the presence of phosphorus oxychloride asboth an activating and dehydrating agent provides thebis-aminothiadiazole E-4. Acylation of E-4 either using by reaction withan acid chloride or by using a suitable amide coupling agent (such asT3P, HATU or HBTU) and an appropriate carboxylic acid in the presence ofa base such as pyridine, TEA or Hunig's base in a solvent such as DMF orDMA affords the symmetrically substituted bis-aminothidiazole, E-5.Separation of the diastereomers and enantiomers may be carried out understandard methods known in the art such as flash chromatography, chiralSFC or HPLC to afford a single diastereomer or enantiomer E-5.

As exemplified in Scheme F, the mono-ester mono-acid A-1 is condensedwith the alkyl or aryl-substituted thiosemicarbazide, F-2, in thepresence of phosphorus oxychloride as both an activating and dehydratingagent to provide the alkyl or aryl-substituted aminothiadiazole F-3. Thealkyl-substituted thiosemicarbazide F-2 is obtained either fromcommercial sources or by the action of hydrazine on a commercial alkylor aryl isothiocyanide, F-1 or by using alternative methods which arewell established in the literature (Phosphorus, Sulfur, and Silicon andthe Related Elements, 1991, 60 (1-2), 15-19). Hydrolysis of the esterF-3 using an inorganic base such as lithium hydroxide or sodiumhydroxide in a solvent such as methanol and water gives the carboxylicacid, F-4. Condensation of F-4 with thiosemicarbazide in the presence ofphosphorus oxychloride as both an activating and dehydrating agentprovides the bis-aminothiadiazole E-5. Acylation of F-5 either using byreaction with an acid chloride or by using a suitable amide couplingagent (such as T3P, HATU or HBTU) and an appropriate carboxylic acid inthe presence of a base such as pyridine, TEA or Hunig's base in asolvent such as DMF or DMA affords the symmetrically substitutedbis-aminothidiazole, F-6. Separation of the enantiomers may be carriedout under standard methods known in the art such as chiral SFC or HPLCto afford single enantiomers of F-6.

As exemplified in Scheme G, the di-acid B-1 may be either obtained fromcommercial sources, or prepared by methods, which are established in theliterature or reported herein. B-1 may be converted to the dihalide G-1through a decarboxylation-halogenation type sequence typically referredto as a Hunsdiecker reaction, which may take place under photochemicalconditions in the presence of a suitable halogen source, such asdiiodohydantoin in a solvent such as 1,2-dichloroethane. The couplingpartner A-5 is obtained from the acylation of a commercially available2-amino-6-halogenated heterocycle, A-4, using an acid in the presence ofa standard coupling reagent such as T3P, HATU or HBTU in the presence ofa base such as pyridine, Hunig's base or TEA. The reaction between A-5and B-1 takes place through a palladium-mediated process such as aNegishi reaction. For example, the di-halogenated compound B-1 may beactivated as an organometallic species such as an organozincate bytreatment with species such as zinc dust in the presence of anactivating agent such a 1,2-dibromoethane and TMS-Cl in a solvent suchas DMF, or without activation by using diethyl zinc for the metallationprocess. The zincate obtained may be coupled with the halogenatedheterocycle A-5 through a Negishi reaction using a palladium catalystsuch as Pd₂(dba)₃ in the presence of a suitable ligand such astri(o-tolylphoshine) in a solvent such as DMF to afford G-2. Ifnecessary, separation of the enantiomers of G-2 may be carried out understandard methods known in the art such as chiral SFC or HPLC to affordthe single enantiomers of G-2.

As exemplified in Scheme H, coupling partner A-5 is obtained from theacylation of a commercially available 2-amino-6-halogenated heterocycle,A-4, using an acid in the presence of a standard coupling reagent suchas T3P, HATU or HBTU in the presence of a base such as pyridine, Hunig'sbase or TEA. Vinyl boronate H-1 may be obtained from an establishedliterature procedure involving borylation of the correspondinghalogenated α,β-unsaturated cyclic ketone (US 2012/0077814). Thereaction between A-5 and H-1 takes place through a palladium-mediatedprocess such as a Suzuki reaction to give H-2. For example, A-5 and H-1may be reacted together at elevated temperature in the presence of apalladium catalyst, such as Pd(dppf)Cl₂ in the presence of suitable base(such as K₃PO₄ or CsF) in a mixed solvent system comprising of anorganic solvent (for example, THF, DME or toluene) and water. Reductionof the endocyclic olefin of H-2 under hydrogen pressure in the presenceof a heterogeneous catalyst such as palladium on carbon or platinumoxide in a solvent such as methanol or dichloromethane gives H-3. H-3may be elaborated to H-4 through a Horner-Wittig-Emmons type olefinationinvolving treatment of with a phosphonate reagent such asdiethyl(cyanomethyl)phosphonate in the presence of a strong base such asNaH in a suitable solvent (for example, THF). Reduction of the exocyclicolefin of H-4 to give H-5 may be achieved through utilization of ahydride-based reagent. For example, L-Selectride may be employed as thereductant in a solvent such as THF at depressed temperature to provideH-5 as a mixture of diastereomers. Condensation of H-5 withthiosemicarbazide in the presence of an acid such as TFA at elevatedtemperature provides the aminothiadiazole H-6. Acylation of H-6 eitherusing by reaction with an acid chloride or by using a suitable amidecoupling agent (such as T3P, HATU or HBTU) and an appropriate carboxylicacid in the presence of a base such as pyridine, TEA or Hunig's base ina solvent such as DMF or DMA affords H-7. Separation of thediastereomers and enantiomers may be carried out under standard methodsknown in the art such as chiral SFC or HPLC to afford the singleenantiomers of H-7.

For some of the steps of the here above described process of preparationof the compounds of the invention, it may be necessary to protectpotential reactive functions that are not wished to react, and to cleavesaid protecting groups in consequence. In such a case, any compatibleprotecting radical may be used. In particular methods of protection anddeprotection such as those described by T. W. Greene (Protective Groupsin Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P.J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), may beused.

All of the above reactions and the preparations of novel startingmaterials used in the preceding methods are conventional and appropriatereagents and reaction conditions for their performance or preparation aswell as procedures for isolating the desired products will be well-knownto those skilled in the art with reference to literature precedents andthe examples and preparations hereto.

Example 1 (Scheme A): Preparation of2-phenyl-N-(6-{[(cis)-3-{5-[(pyridine-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide

Step 1: Preparation ofmethyl-(cis)-3-(hydroxymethyl)cyclopentanecarboxylate

To a solution of (cis)-3-(methoxycarbonyl)cyclopentanecarboxylic acid(2.7 g, 15.7 mmol) in THF (42 mL) was added borane dimethylsulfidecomplex (2.5 mL, 26 mmol) dropwise at −78° C. The reaction mixture waswarmed to 0° C. and stirred for 1 hr at this temperature. The reactionwas stirred at room temperature for 3 hr, cooled back to −20° C. andquenched with 1 M KH₂PO₄. The resulting reaction mixture was warmed toroom temperature, stirred for 20 min and extracted with Et₂O (3×100 mL).Then, the combined organics were washed with brine, dried over Na₂SO₄and concentrated down to give the title compound (2.3 g, 55%) as a clearoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.68 (s, 3H), 3.59 (dd, J=6.5, 2.1Hz, 2H), 2.81 (quin, J=8.2 Hz, 1H), 2.13-2.26 (m, 1H), 2.02-2.13 (m,1H), 1.84-1.96 (m, 2H), 1.72-1.84 (m, 1H), 1.44-1.58 (m, 2H). m/z(APCl+) for C₈H₁₄O₃ 159.2 (M+H)⁺.

Step 2: Preparation ofmethyl-(cis)-3-(iodomethyl)cyclopentanecarboxylate

To a mixture of PPh₃ (1.0 g, 3.74 mmol) and imidazole (255 mg, 3.74mmol) in CH₂Cl₂ (14 mL) was added I₂ (954 mg, 3.74 mmol) portionwise atroom temperature. The resulting orange suspension was treated slowlywith a solution of methyl-(cis)-3-(hydroxymethyl)cyclopentanecarboxylate(538 mg, 3.4 mmol) in CH₂Cl₂ (4 mL) and then stirred at room temperaturefor 14 hr. Then, the reaction mixture was washed with aq. Na₂S₂O₃ andextracted with CH₂Cl₂. The combined organics were dried over Na₂SO₄ andevaporated to give the crude title compound. The crude residue wasdiluted with heptanes and the solids filtered to removetriphenylphosphine oxide. The filtrate was evaporated to give a clearoil which was then purified by flash chromatography with a gradient of0%-15% CH₂Cl₂ in heptanes to givemethyl-(cis)-3-(iodomethyl)cyclopentanecarboxylate (718 mg, 79%) as aclear oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.69 (s, 3H), 3.23 (d, J=6.80Hz, 2H), 2.81-2.92 (m, 1H), 2.16-2.33 (m, 2H), 1.86-2.02 (m, 3H),1.51-1.55 (m, 1H), 1.38-1.49 (m, 1H).

Step 3: Preparation of N-(6-iodopyridazin-3-yl)-2-phenylacetamide

To a solution of 5-iodopyridazin-3-amine (1.3 g, 5.7 mmol) in DMF (6.7mL) was added dropwise diisopropylethylamine (1.14 mL, 6.83 mmol)followed by phenylacetyl chloride (0.9 mL, 6.83 mmol) at 0° C. Then, thereaction mixture was slowly warmed to room temperature overnight. Theresulting solution was diluted with water, filtered off and rinsed withwater to give the title compound (1.18 g, 61%) as a tan powder. ¹H NMR(400 MHz, CDCl₃) δ ppm 3.84 (s, 2H), 7.34-7.44 (m, 5H), 7.82 (d, J=9.32Hz, 1H), 8.25 (d, J=9.32 Hz, 1H). m/z (APCl+) for C₁₂H₁₀IN₃O 340.1(M+H)⁺.

Step 4: Preparation of(cis)-3-({6-[(phenlyacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylate

To a suspension of Zn dust (226 mg, 3.45 mmol) in dry degassed DMF (0.5mL) was added 1,2-dibromoethane (11 μL, 0.12 mmol) under N₂. Then, themixture was heated with a heat gun for about 30 sec until gas evolutionwas observed from the solution, indicating the activation of Zn. Themixture was allowed to cool to room temperature, followed by theaddition of TMSCl (16 μL, 0.13 mmol) and allowed to stir at roomtemperature for 30 min. A solution ofmethyl-(cis)-3-(iodomethyl)cyclopentanecarboxylate (308 mg, 1.15 mmol)in DMF (1 mL) was added to the Zn solution, and then the resultingmixture was stirred at room temperature for 1 hr. After allowing the Znto settle, the reaction mixture was filtered through a syringe filterinto a mixture of N-(6-iodopyridazin-3-yl)-2-phenylacetamide (195 mg,0.58 mmol), Pd₂(dba)₃ (105 mg, 0.12 mmol), and tri(o-tolyl)phosphine (70mg, 0.23 mmol) in DMF (2.3 mL). The reaction mixture was flushed withN₂, and stirred at 40° C. for 50 min. Then, Si-Thiol was added to thewarm reaction mixture to remove Pd residues. After 20 min at 40° C., themixture ws diluted with EtOAc and filtered off to remove the Si-Thiol.The filtrate was washed with water twice followed by brine and driedover Na₂SO₄. Purification via flash chromatography with a gradient of0%-55% EtOAc in heptanes afforded(cis)-3-({6-[(phenylacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylate(69 mg, 34% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.63(d, J=9.3 Hz, 1H), 7.52 (d, J=9.3 Hz, 1H), 7.36-7.45 (m, 5H), 3.92 (s,2H), 3.68 (s, 3H), 2.99 (d, J=7.30 Hz, 2H), 2.74-2.87 (m, 1H), 2.31-2.44(m, 1H), 2.02-2.12 (m, 1H), 1.86-1.99 (m, 2H), 1.73-1.85 (m, 1H),1.49-1.60 (m, 1H), 1.37-1.49 (m, 1H). m/z (APCl+) for C₂₀H₂₃N₃O₃ 354.3(M+H)⁺.

Step 5: Preparation of(cis)-3-({6-[(phenylacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylicacid

To a solution of(cis)-3-({6-[(phenylacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylate(205 mg, 0.58 mmol) in a mixture of MeOH (5 mL), water (1.5 mL) and THF(3 mL) was added LiOH (111 mg, 4.64 mmol) at room temperature. After 1hr, the reaction mixture was evaporated to remove solvent, and washedwith Et₂O. Then, the aq. layer was acidified with 1 N HCl to pH 2. Theresulting solid was filtered off, washed with water and dried undervacuum to give the title compound (96 mg, 49%) as a white solid. m/z(APCl+) for C₁₉H₂₁N₃O₃ 340.3 (M+H)⁺.

Step 6: Preparation ofN-[6-({(cis)-3-[(2-carbamothioylhydrazinyl)carbonyl]cyclopentyl}methyl)pyridazin-3-yl]-2-phenylacetamide

To a mixture of(cis)-3-({6-[(phenylacetyl)amino]pyridazin-3-yl}methyl)cyclopentanecarboxylicacid (96 mg, 0.28 mmol) and HATU (170 mg, 0.42 mmol) in DMF (1.4 mL) wasadded Et₃N (79 μL, 0.57 mmol) at room temperature. After 10 min, theresulting mixture was treated with thiosemicarbazide (39 mg, 0.42 mmol)and stirred for 40 min at room temperature. Then, the reaction mixturewas evaporated under vacuum to remove DMF. The crude compound was useddirectly for the next step without further purification. m/z (APCl+) forC₂₀H₂₄N₆O₂S 413.3 (M+H)⁺.

Step 7: Preparation ofN-[6-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)-2-phenylacetamide

N-[6-({(cis)-3-[(2-carbamothioylhydrazinyl)carbonyl]cyclopentyl}methyl)pyridazin-3-yl]-2-phenylacetamide(120 mg, 0.29 mmol) was treated with neat sulfuric acid (0.58 mL) at 0°C. After 30 min at 0° C., the reaction mixture was added dropwise to asolution of ice-cold aq. NaHCO₃. The resulting mixture was extractedwith CH₂Cl₂ four times, and dried over Na₂SO₄. Purification via flashchromatography with a gradient of 0%-10% MeOH in CH₂Cl₂ affordedN-[6-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)-2-phenylacetamide(44 mg, 38% yield) as a yellow solid. m/z (APCl+) for C₂₀H₂₂N₆OS 395.3(M+H)⁺.

Step 8: Preparation of2-phenyl-N-(6-{[(cis)-3-{5-[(pyridine-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide

To a mixture ofN-[6-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3-yl)-2-phenylacetamide(44 mg, 0.11 mmol) and HATU (54 mg, 0.13 mmol) in DMF (2.2 mL) was addedEt₃N (63 μL, 0.45 mmol) at room temperature. Then, the resulting mixturewas treated with 2-pyridyl acetic acid hydrochloride (22 mg, 0.12 mmol),and it was stirred for 2 hr at room temperature. The crude was purifiedby reverse phase chromatography eluting with MeCN:water (5:95 to 95:5)to give2-phenyl-N-(6-{[(cis)-3-{5-[(pyridine-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}pyridazin-3-yl)acetamide(18 mg, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.63 (brs, 1H), 11.22 (s, 1H), 8.49 (d, J=4.78 Hz, 1H), 8.19 (d, J=9.06 Hz, 1H),7.76 (td, J=7.68, 1.76 Hz, 1H), 7.56 (d, J=9.32 Hz, 1H), 7.19-7.43 (m,7H), 3.99 (s, 2H), 3.76 (s, 2H), 3.44-3.55 (m, 1H), 2.94 (d, J=7.30 Hz,2H), 2.03-2.28 (m, 3H), 1.74-1.91 (m, 2H), 1.42-1.60 (m, 2H). m/z(APCl+) for C₂₇H₂₇N₇O₂S 514.1 (M+H)⁺.

Example 2A (Scheme B): Preparation of2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide

Step 1: Preparation of5-(((1R,3S)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine

To a flask containing (1 S,3R)-3-(carboxymethyl)cyclopentane carboxylicacid (11.4 g, 66.2 mmol) and ground thiosemicarbazide (13.9 g, 152 mmol)was added slowly in a drop-wise manner POCl₃ until a slurry was formed,then the remainder of POCl₃ (60.8 mL total, 652 mmol) was added. Themixture was then stirred for 30 min at 80° C. with a strong exothermbeing observed upon initial heating. The reaction was then allowed tocool to room temperature and then added dropwise to cold 3 M NaOH (1.32L). The solids formed were filtered off, rinsed with water and driedovernight under vacuum. Trituration with EtOH followed by filtrationafforded5-(((1R,3S)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine(12.25 g, 66%) as a tan solid. (400 MHz, DMSO-d₆) δ ppm 6.97 (s, 4H),3.27-3.34 (m, 1H), 2.85 (d, J=7.2 Hz, 2H), 2.13-2.38 (m, 2H), 1.94-2.10(m, 1H), 1.72-1.89 (m, 2H), 1.32-1.52 (m, 2H) ppm. m/z (ESI+) forC₁₀H₁₄N₆S₂ 283.17 (M+H)⁺.

Step 2: Preparation of2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide

Pyridine (60 mL, 730 mmol) was added to a mixture of5-(((1R,3S)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine(12.25 g, 43.4 mmol) and 2-pyridylacetic acid hydrochloride (18.8 g, 108mmol). After stirring for 5 min, T3P (72.3 mL, 50% in DMF, 121 mmol) wasadded. Upon addition, a minor exotherm was observed, accompanied byeffervesence. The reaction was stirred for 15 min and then checked byLCMS. The mono-acylated product was still observed, and as suchadditional 2-pyridylacetic acid hydrochloride (5 g, 28.7 mmol), T3P (10mL, 50% in DMF, 16.7 mmol) and pyridine (20 mL, 243 mmol) were added andthe reaction stirred overnight. The reaction was concentrated to removeexcess pyridine, and then the residue was added dropwise to water withstirring. After addition was complete, the mixture was brought to pH˜7.5 and the solids filtered off, and rinsed with water. The solids weretriturated with acetone and filtered to give2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide(14.6 g, 65%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.65(br s, 2H), 8.49 (d, J=4.77 Hz, 2H), 7.77 (td, J=7.6, 1.9 Hz, 2H), 7.39(d, J=7.8 Hz, 2H), 7.28 (ddd, J=7.6, 4.9, 1.2 Hz, 2H), 4.00 (s, 4H),3.50 (dt, J=10.3, 7.7 Hz, 1H), 3.07 (d, J=7.3 Hz, 2H), 2.35-2.47 (m,1H), 2.29 (dt, J=13.5, 7.1 Hz, 1H), 2.12 (dtd, J=15.9, 8.9, 7.7, 3.8 Hz,1H), 1.76-1.96 (m, 2H), 1.44-1.61 (m, 2H). m/z (ESI+) for C₂₄H₂₄N₈O₂S₂521.1 (M+H)⁺.

Example 2B: Preparation of2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[{pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamideDihydrochloride

2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentylmethyl}-1,3,4-thiadiazol-2-yl)acetamide (10 g, 19.2 mmol) wasstirred in MeOH (100 mL) at room temperature before HCl (3.47 mL, 42.3mmol) was added in a drop-wise fashion. The solution was heated to 65°C. for 1 hr. The slurry was allowed to cool to room temperature, and thecolorless solids were filtered, rinsed with MeOH and dried to give2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide (11.25 g, 98%) as thebis-HCl salt, which was shown to be a mono-hydrate by CHN analysis. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 13.00 (br s, 2H), 8.70-8.80 (m, 2H),8.21-8.30 (m, 2H), 7.68-7.81 (m, 4H), 4.28 (s, 4H), 3.43-3.52 (m, 1H),3.11-3.43 (m, 2H), 2.28-2.49 (m, 2H), 2.12-2.17 (m, 1H), 1.81-1.90 (m,2H), 1.41-1.61 (m, 2H). m/z (ESI+) for C₂₄H₂₄N₈O₂S₂ 521.1 (M+H)⁺.

The absolute stereochemistry of the final compounds was determined byprocessing the racemic (cis)-di-acid through the identical chemicalsequence as described below.

Step 1: Preparation of5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine

Cis-3-(carboxymethyl)cyclopentane carboxylic acid (12.0 g, 63.89 mmol)and thiosemicarbazide (11.64 g, 127.77 mmol) were combined and POCl₃ (80mL) was added. The reaction mixture was heated at 100° C. for 3 hr togive a yellow solution, which was then cooled to room temperature. Thecrude was quenched in warm water and basified to pH 7 with NaOH 50%. Theresulting solid was filtered off, washed well with water and dried at60° C. under vacuum to give5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amineas a white solid (17.0 g, 86%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.00 (s,4H), 3.27-3.34 (m, 1H), 2.85 (d, J=7.2 Hz, 2H), 2.13-2.38 (m, 2H),1.94-2.10 (m, 1H), 1.72-1.89 (m, 2H), 1.32-1.52 (m, 2H) ppm. m/z (ESI+)for C₁₀H₁₄N₆S₂ 283.17 (M+H)⁺.

Step 2: Preparation of2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamideExample 2

5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine(273 mg, 0.97 mmol) and 2-pyridine acetic acid hydrochloric acid salt(369 mg, 2.13 mmol) were slurried in DMF (3 mL) with HATU (882 mg, 2.32mmol). DIPEA (0.74 mL, 4.2 mmol) was added and the resultant yellowsolution stirred at room temperature under nitrogen overnight. Oncereaction completion was confirmed, water (20 mL) was added and thereaction was extracted three times with CH₂Cl₂:MeOH (20 mL, 90:10). Thecombined organics were washed with saturated brine and stripped toafford an oil. This was purified first with flash chromatography elutingwith CH₂CO₂:MeOH (97:3 to 90:10) to give 140 mg of an oily solid. Thiswas then purified by reverse phase chromatography eluting withMeCN:water with 0.1% NH₃ (5:95 to 95:5) to give racemic Example 3 as anoff white solid (47 mg, 9%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.68 (s,2H), 8.45-8.52 (m, 2H), 7.77 (td, J=7.6, 1.9 Hz, 2H), 7.39 (d, J=7.8 Hz,2 H), 7.28 (ddd, J=7.6, 4.9, 1.2 Hz, 2H), 4.00 (s, 4H), 3.50 (dt,J=10.3, 7.7 Hz, 1H), 3.07 (d, J=7.3 Hz, 2H), 2.35-2.47 (m, 1H), 2.29(dt, J=13.5, 7.1 Hz, 1H), 2.12 (dtd, J=15.9, 8.9, 7.7, 3.8 Hz, 1H),1.76-1.96 (m, 2H), 1.40-1.63 (m, 2H). m/z (ESI+) for C₂₄H₂₄N₈O₂S₂ 521.1(M+H)⁺.

19 mg was subjected to chiral separation by SFC to afford bothenantiomers. The analytical chiral separation by SFC was performed usinga Chiralcel OJ-H column (4.6 mm×100 mm column, 3 micron particle size),which was eluted with 30% MeOH (with 0.1% DEA) in CO₂ held at 120 bar. Aflow rate of 4 mL/min gave Rt_((Peak 1))=1.60 minutes andRt_((Peak2))=1.98 minutes.

Example 4 (Peak 1): 2 mg, 99% ee (−). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.68 (s, 2H), 8.45-8.52 (m, 2H), 7.77 (td, J=7.6, 1.9 Hz, 2H), 7.39 (d,J=7.8 Hz, 2H), 7.28 (ddd, J=7.6, 4.9, 1.2 Hz, 2H), 4.00 (s, 4H), 3.50(dt, J=10.3, 7.7 Hz, 1H), 3.07 (d, J=7.3 Hz, 2H), 2.35-2.47 (m, 1H),2.29 (dt, J=13.5, 7.1 Hz, 1H), 2.12 (dtd, J=15.9, 8.9, 7.7, 3.8 Hz, 1H),1.76-1.96 (m, 2H), 1.40-1.63 (m, 2H). m/z (ESI+) for C₂₄H₂₄N₈O₂S₂ 521.1(M+H)⁺.

Example 2 (Peak 2): 2 mg, 98% ee (+). ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.68 (s, 2H), 8.45-8.52 (m, 2H), 7.77 (td, J=7.6, 1.9 Hz, 2H), 7.39 (d,J=7.8 Hz, 2H), 7.28 (ddd, J=7.6, 4.9, 1.2 Hz, 2H), 4.00 (s, 4H), 3.50(dt, J=10.3, 7.7 Hz, 1H), 3.07 (d, J=7.3 Hz, 2H), 2.35-2.47 (m, 1H),2.29 (dt, J=13.5, 7.1 Hz, 1H), 2.12 (dtd, J=15.9, 8.9, 7.7, 3.8 Hz, 1H),1.76-1.96 (m, 2H), 1.40-1.63 (m, 2H). m/z (ESI+) for C₂₄H₂₄N₈O₂S₂ 521.1(M+H)⁺.

Crystals of Example 4 were grown by vapor diffusion of ether into an80/20 dichloromethane/methanol solution, and were subjected to singlecrystal X-ray diffraction studies to obtain the absolute stereochemistryof the cyclopentane ring junction. Example 4 was shown to be2-(pyridin-2-yl)-N-(5-{[(1S,3R)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide,thus enabling the assignment of Example 2 as2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide.In addition, chiral SFC separation of5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine,and subsequent derivatization to Example 4 and Example 2 enabledassignment of the stereochemistry of this intermediate for thepreparation of enantiopure analogues.

Example 5 (Scheme B): Preparation of N-[5-({(1R,3S)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide

5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine(200 mg, 0.708 mmol) suspended in DMA (2 mL) was addeddimethylaminopyridine (173 mg, 1.416 mmol), followed by acetyl chloride(151 μL, 2.124 mmol). The reaction was stirred at room temperature for16 hr to give a suspension, which was then diluted with water (7 mL).The resultant solid was filtered off, washed well with water, and driedat 60° C. under vacuum to give 194 mg of a fawn solid. After beingdissolved in hot DMSO (2 mL), the compound was purified viareverse-phase chromatography, eluting with 5-100% MeCN in 0.1% aq.formic acid to provide racemic Example 6 as a colorless solid (38 mg,15% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.38 (s, 2H), 3.57 (m, 1H),3.07 (d, J=7.4 Hz, 2H), 2.42 (dq, J=9.8, 7.6 Hz, 1H), 2.29 (dt, J=13.4,7.0 Hz, 1H), 2.16 (d, J=1.2 Hz, 6H), 2.09-2.14 (m, 1H), 1.78-1.95 (m,2H), 1.43-1.62 (m, 2H). m/z (ESI+) for C₁₄H₁₈N₆O₂S₂ 367.12 (M+H)⁺. 11 mgwas subjected to chiral separation by SFC to afford both enantiomers.The analytical chiral separation by SFC was performed using a ChiralpakAS-H column (4.6 mm×250 mm column, 5 micron particle size), which waseluted with 30% MeOH (with 0.1% DEA) in CO₂ held at 140 bar. A flow rateof 3 mL/min gave Rt_((Peak 1))=3.00 minutes and Rt_((Peak 2))=4.62minutes.

Example 5 (Peak 1): 3.89 mg, >98% ee. ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.38 (s, 2H), 3.57 (m, 1H), 3.07 (d, J=7.4 Hz, 2H), 2.42 (dq, J=9.8,7.6 Hz, 1H), 2.29 (dt, J=13.4, 7.0 Hz, 1H), 2.16 (d, J=1.2 Hz, 6H),2.09-2.14 (m, 1H), 1.78-1.95 (m, 2H), 1.43-1.62 (m, 2H). m/z (ESI+) forC₁₄H₁₈N₆O₂S₂ 367.12 (M+H)⁺.

Example 7 (Peak 2): 3.72 mg, >98% ee. ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.38 (s, 2H), 3.57 (m, 1H), 3.07 (d, J=7.4 Hz, 2H), 2.42 (dq, J=9.8,7.6 Hz, 1H), 2.29 (dt, J=13.4, 7.0 Hz, 1H), 2.16 (d, J=1.2 Hz, 6H),2.09-2.14 (m, 1H), 1.78-1.95 (m, 2H), 1.43-1.62 (m, 2H). m/z (ESI+) forC₁₄H₁₈N₆O₂S₂ 367.12 (M+H)⁺.

Example 8 (Scheme B): Preparation of 2-phenyl-N-(5-{[(1R,3S)-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide

To5-(((cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl)methyl)-1,3,4-thiadiazol-2-amine(200 mg, 0.708 mmol) suspended in DMA (2 mL) was addeddimethylaminopyridine (87 mg, 0.708 mmol), followed by phenylacetylchloride (281 μL, 2.124 mmol). The reaction was stirred at roomtemperature for 64 hr to give a clear solution. Water (3 mL) was added,and the mixture stirred for 30 min to give a fawn solid, which wasfiltered, washed with water and dried. This solid was dissolved in DMSO(2 mL) and water (4 mL) added to re-precipitate the product, which wasfiltered off, washed well with water and dried at 60° C. under vacuum togive racemic Example 9 (225 mg, 55% yield) as a fawn solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.66 (s, 2H), 6.72-7.88 (m, 10H), 3.78 (d, J=1.5Hz, 4H), 3.49 (dd, J=10.0, 7.5 Hz, 1H), 3.05 (d, J=7.3 Hz, 2H),2.34-2.47 (m, 1H), 2.26 (dt, J=13.0, 6.9 Hz, 1H), 2.03-2.17 (m, 1H),1.76-1.93 (m, 2H), 1.41-1.60 (m, 2H). m/z (ESI+) for C₂₆H₂₆N₆O₂S₂ 519.24(M+H)⁺.

190 mg was subjected to chiral separation by SFC to afford bothenantiomers. The analytical chiral separation by SFC was performed usinga Chiralpak AS-H column (4.6 mm×250 mm column, 5 micron particle size),which was eluted with 40% MeOH (with 0.1% DEA) in CO₂ held at 140 bar. Aflow rate of 3 mL/min gave Rt_((Peak 1))=8.51 minutes andRt_((Peak 2))=10.20 minutes.

Example 8 (Peak 1): 60.83 mg, >99% ee (+). ¹H NMR (400 MHz, DMSO-d₆) δppm 12.66 (s, 2H), 6.72-7.88 (m, 10H), 3.78 (d, J=1.5 Hz, 4H), 3.49 (dd,J=10.0, 7.5 Hz, 1H), 3.05 (d, J=7.3 Hz, 2H), 2.34-2.47 (m, 1H), 2.26(dt, J=13.0, 6.9 Hz, 1H), 2.03-2.17 (m, 1H), 1.76-1.93 (m, 2H),1.41-1.60 (m, 2H). m/z (ESI+) for C₂₆H₂₆N₆O₂S₂ 519.24 (M+H)⁺.

Example 10 (Peak 2): 61.32 mg, 99% ee (−). ¹H NMR (400 MHz, DMSO-d₆) δppm 12.66 (s, 2H), 6.72-7.88 (m, 10H), 3.78 (d, J=1.5 Hz, 4H), 3.49 (dd,J=10.0, 7.5 Hz, 1H), 3.05 (d, J=7.3 Hz, 2H), 2.34-2.47 (m, 1H), 2.26(dt, J=13.0, 6.9 Hz, 1H), 2.03-2.17 (m, 1H), 1.76-1.93 (m, 2H),1.41-1.60 (m, 2H). m/z (ESI+) for C₂₆H₂₆N₆O₂S₂ 519.24 (M+H)⁺.

Example 11 (Scheme C): Preparation ofN-{5-[3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide

Step 1: Preparation of methyl[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]acetate

(Cis)-3-(2-methoxy-2-oxoethyl)cyclopentanecarboxylic acid (10 g, 53.7mmol) and thiosemicarbazide (5.45 g, 59.0 mmol) were suspended in POCl₃(50 mL) and heated to reflux for 40 min, during which the suspensionbecame a clear yellow solution. The mixture was allowed to cool,evaporated in vacuo, and then azeotoped three times with toluene toremove POCl₃ residues. The resulting amber oil was carefully quenchedwith saturated NaHCO₃ solution (350 mL), and then extracted into EtOAc(2×300 mL). The combined organic extracts were dried over MgSO₄, andevaporated to afford a yellow solid (10.3 g). This was purified by flashchromatography (eluting 0-10% methanol in EtOAc) to afford methyl[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]acetate as an offwhite solid (6.3 g, 49% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.00 (s,2H), 3.58 (s, 3H), 3.25-3.33 (m, 1H), 2.40 (d, J=2.3 Hz, 1H), 2.39 (d,J=1.1 Hz, 1H), 2.16-2.35 (m, 2H), 1.97-2.05 (m, 1H), 1.81-1.91 (m, 1H),1.68-1.80 (m, 1H), 1.28-1.41 (m, 2H). m/z (APCl+) for C₁₀H₁₅N₃O₂S 242.1(M+H)⁺.

Step 2: Preparation of methyl{(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate

To a solution of methyl[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]acetate (1.8 g, 7.46mmol) in CH₂Cl₂ (20 mL) under nitrogen at room temperature was addedEt₃N (2.08 mL, 14.9 mmol) followed by acetyl chloride (0.58 mL, 8.20mmol). The resulting yellow suspension was stirred for 4 hr then washedwith water. The organic layer was separated, washed with brine, driedover Na₂SO₄ and evaporated to give a methyl{(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate(2.15 g, 100%) as a cream solid. ¹H NMR (400 MHz, MeOH-d₄) δ ppm 3.70(s, 3H), 3.47-3.63 (m, 1 H), 2.40-2.58 (m, 4H), 2.26 (s, 3H), 1.90-2.14(m, 3H), 1.48-1.63 (m, 2H). m/z (APCl+) for C₁₂H₁₇N₃O₃S 284.1 (M+H)⁺.

Step 3: Preparation of{(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid

To a solution of methyl{(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate(2.11 g, 7.447 mmol) in MeOH (30 mL) was added aq. 3 M lithium hydroxidesolution (5.0 mL, 14.9 mmol). The solution was stirred at 45° C. for 4hr, and then concentrated to remove the MeOH followed by acidificationto pH 4 with 1 M AcOH. The resulting solution was extracted with EtOAc(3×30 mL), and the combined organic layers washed with brine. Theorganics were dried over Na₂SO₄, filtered, and evaporated under vacuumto yield{(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid(1.7 g, 85%) as a cream solid. m/z (APCl+) for C₁₁H₁₅N₃O₃S 270.5 (M+H)⁺.

Step 4: Preparation ofN-{5-[(cis)-3-(2-hydrazinyl-2-oxoethyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide

To a solution of{(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid(450 mg, 1.67 mmol) in dry DMF (10 mL) was added HBTU (711 mg, 1.84mmol) and Et₃N (0.35 mL, 2.51 mmol). The resulting clear yellow solutionwas stirred for 1 hr, then hydrazine (0.09 mL, 2.51 mmol) was added andthe solution stirred for a further 3 hr. The mixture was concentrated togive a cream solid, which was slurried in CH₂Cl₂ (40 mL) and filteredunder vacuum. The solid was washed with more CH₂Cl₂ and dried undervacuum to giveN-{5-[(cis)-3-(2-hydrazinyl-2-oxoethyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide(447 mg 94%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.93(brs, 1H), 4.17 (brs, 2H), 3.40-3.53 (m, 1H), 2.20-2.38 (m, 2H), 2.16(s, 3H), 2.03-2.14 (m, 3H), 1.74-1.90 (m, 2H), 1.31-1.50 (m, 2H). m/z(APCl+) for C₁₁H₁₇N₅O₂S 284.1 (M+H)⁺.

Step 5: Preparation ofN-{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]carbonothioyl}benzamide

To a solution ofN-{5-[(cis)-3-(2-hydrazinyl-2-oxoethyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide(50 mg, 0.18 mmol) in (2 mL) was added benzoylisothiocyanate (0.028 mL,0.211 mmol) and the suspension stirred at 40° C. for 3 hr. The mixturewas cooled and filtered under vacuum. The solid was washed with EtOAcfollowed by CH₂Cl₂ to giveN-{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]carbonothioyl}benzamide(58 mg, 74%) as a cream solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.60 (d,J=4.40 Hz, 1H), 12.37 (s, 1H), 11.67 (s, 1H), 10.83 (d, J=4.40 Hz, 1H),7.95 (d, J=7.34 Hz, 2H), 7.64 (m, J=7.30 Hz, 1H), 7.52 (t, J=1.00 Hz,2H), 3.44-3.58 (m, 1H), 2.28-2.45 (m, 4H), 2.06-2.21 (m, 4H), 1.88 (m,J=7.30 Hz, 2H), 1.43-1.60 (m, 2H). m/z (APCl+) for C₂₀H₂₄N₆O₃S₂ 447.1(M+H)⁺.

Step 6: Preparation ofN-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide(Example 11)

N-{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]carbonothioyl}benzamide(58 mg, 0.13 mmol) was stirred in ice cold sulfuric acid (3 mL) for 3hr. The clear solution was slowly added to ice cold water (10 mL) givingan oily suspension. EtOAc (10 mL) was added and the mixture stirredgiving a cream solid. The mixture was filtered under vacuum and thesolid washed with water followed by heptanes to giveN-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide(25 mg, 45%, Example 11) as a cream solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 12.89 (br s, 1H), 12.35 (br s, 1H), 8.10 (d, J=7.46 Hz, 2H),7.62-7.71 (m, 1H), 7.50-7.60 (m, 2H), 3.45-3.61 (m, 1H), 3.12 (d, J=7.09Hz, 2H), 2.27-2.40 (m, 1H), 2.07-2.24 (m, 4H), 1.81-2.02 (m, 2H),1.48-1.69 (m, 2H). m/z (APCl+) for C₁₉H₂₀N₆O₂S₂ 429.1 (M+H)⁺.

16 mg was subjected to chiral separation by SFC to afford bothenantiomers. The analytical chiral separation by SFC was performed usinga Chiralpak OJ-H column (4.6 mm×250 mm column, 5 micron particle size),which was eluted with 30% MeOH in CO₂ held at 140 bar. A flow rate of 3mL/min gave Rt_((Peak 1))=4.63 minutes and Rt_((Peak 2))=5.57 minutes.

Example 12 (Peak 1): 5.15 mg, >99% ee. ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.89 (brs, 1H), 12.35 (brs, 1H), 8.10 (d, J=7.46 Hz, 2H), 7.62-7.71 (m,1H), 7.50-7.60 (m, 2H), 3.45-3.61 (m, 1H), 3.12 (d, J=7.09 Hz, 2H),2.27-2.40 (m, 1H), 2.07-2.24 (m, 4H), 1.81-2.02 (m, 2H), 1.48-1.69 (m,2H). m/z (APCl+) for C₁₉H₂₀N₆O₂S₂ 429.1 (M+H)⁺.

Example 13 (Peak 2): 5.65 mg, 99% ee. ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.89 (brs, 1H), 12.35 (brs, 1H), 8.10 (d, J=7.46 Hz, 2H), 7.62-7.71 (m,1H), 7.50-7.60 (m, 2H), 3.45-3.61 (m, 1H), 3.12 (d, J=7.09 Hz, 2H),2.27-2.40 (m, 1H), 2.07-2.24 (m, 4H), 1.81-2.02 (m, 2H), 1.48-1.69 (m,2H). m/z (APCl+) for C₁₉H₂₀N₆O₂S₂ 429.1 (M+H)⁺.

Example 14 (Scheme C): Preparation ofN-[5-({(1R,3S)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide

Step 1: Preparation ofN-{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]carbonothioyl}-2-phenylacetamide

To a solution of the product of Example 5, step 4,N-{5-[(cis)-3-(2-hydrazinyl-2-oxoethyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide(100 mg, 0.353 mmol) in EtOAc (2 mL) was added phenylacetylisothiocyanate (75 mg, 0.424 mmol) and the suspension stirred at 40° C.for 3 hr. The mixture was cooled and filtered under vacuum. The solidwas washed with EtOAc to give a 50% pure sample ofN-{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]carbonothioyl}-2-phenylacetamide(147 mg, 91%) as a brown solid. m/z (APCl+) for C₂₀H₂₄N₆O₃S₂ 460.9(M+H)+, 483 (M+Na)⁺.

Step 2: Preparation ofN-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide(Example 14)

The 50% pure sample ofN-{[2-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetyl)hydrazinyl]carbonothioyl}-2-phenylacetamide(147 mg, 0.16 mmol) was stirred in ice cold sulfuric acid (3 mL) for 3hr. The clear solution was slowly added to ice cold water (10 mL) givinga brown solid, which was filtered under vacuum and washed with waterfollowed by heptane. The brown solid was purified by preparative HPLC toafford racemicN-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide(33 mg, 44%, Example 15 as a cream solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 12.46 (br s, 2H), 7.16-7.42 (m, 5H), 3.79 (s, 2H), 3.43-3.58 (m,1H), 3.06 (d, J=7.34 Hz, 2H), 2.36-2.47 (m, 1H), 2.28 (d, J=12.35 Hz,1H), 2.16 (s, 4H), 1.78-1.99 (m, 2H), 1.41-1.64 (m, 2H). m/z (APCl+) forC₂₀H₂₂N₆O₂S₂ 443.0 (M+H)⁺.

20 mg was subjected to chiral separation by SFC to afford bothenantiomers. The analytical chiral separation by SFC was performed usinga Chiralpak OJ-H column (4.6 mm×250 mm column, 5 micron particle size),which was eluted with 40% MeOH in CO₂ held at 120 bar. A flow rate of 3mL/min gave Rt_((Peak 1))=4.54 minutes and Rt_((Peak 2))=7.67 minutes.

Example 16 (Peak 1): 6.89 mg, >99% ee (−). ¹H NMR (400 MHz, DMSO-d₆) δppm 12.46 (br s, 2H), 7.16-7.42 (m, 5H), 3.79 (s, 2H), 3.43-3.58 (m,1H), 3.06 (d, J=7.34 Hz, 2H), 2.36-2.47 (m, 1H), 2.28 (d, J=12.35 Hz,1H), 2.16 (s, 4H), 1.78-1.99 (m, 2H), 1.41-1.64 (m, 2H). m/z (APCl+) forC₂₀H₂₂N₆O₂S₂ 443.0 (M+H)⁺.

Example 14) (Peak 2): 6.98 mg, >99% ee (+). ¹H NMR (400 MHz, DMSO-d₆) δppm 12.46 (br s, 2H), 7.16-7.42 (m, 5H), 3.79 (s, 2H), 3.43-3.58 (m,1H), 3.06 (d, J=7.34 Hz, 2H), 2.36-2.47 (m, 1H), 2.28 (d, J=12.35 Hz,1H), 2.16 (s, 4H), 1.78-1.99 (m, 2H), 1.41-1.64 (m, 2H). m/z (APCl+) forC₂₀H₂₂N₆O₂S₂ 443.0 (M+H)⁺.

Example 17 (Scheme C): Preparation ofN-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide

Step 1: Preparation ofN-(5-{(cis)-3-[2-(2-carbamothioylhydrazinyl)-2-oxoethyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide

To a solution of{(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid(700 mg, 2.60 mmol) in dry DMF (10 mL) was added HBTU (1.51 g, 3.90mmol) and Et₃N (0.73 mL, 5.20 mmol). The resulting clear yellow solutionwas stirred for 1 hr before thiosemicarbazide (359 mg, 3.90 mmol) wasadded, and the solution then stirred overnight. The reaction wasconcentrated to give a yellow slurry to which CH₂Cl₂ (40 mL) was addedto afford a cream solid. The solid was filtered under vacuum and washedwith CH₂Cl₂ and dried to giveN-(5-{(cis)-3-[2-(2-carbamothioylhydrazinyl)-2-oxoethyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide(671 mg, 75%) as a white powder. m/z (APCl+) for C₁₂H₁₈N₆O₂S₂ 343.05(M+H)⁺.

Step 2: Preparation ofN-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide

N-(5-{(cis)-3-[2-(2-carbamothioylhydrazinyl)-2-oxoethyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide(671 mg, 1.96 mmol) was stirred in ice cold sulfuric acid (3 mL) for 3hr. The clear solution was slowly added to an ice cold aqueous solutionof NaHCO₃ to adjust to pH 8 (Caution—vigorous gas evolution). Theresulting solid was filtered under vacuum and washed well with water togiveN-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide(449 mg, 71%) as a cream powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.96(s, 2H), 3.47-3.53 (m, 1H), 2.88 (d, J=7.30 Hz, 2H), 2.23-2.39 (m, 2H),2.06-2.16 (m, 4H), 1.79-1.94 (m, 2H), 1.42-1.58 (m, 2H). m/z (APCl+) forC₁₂H₁₆N₆OS₂ 325.05 (M+H)⁺.

Step 3: Preparation ofN-[5-({(1R,3S)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide(Example 17)

To a solution ofN-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)acetamide(95 mg, 0.29 mmol) in dry DMF (2 mL) was added HBTU (136 mg, 0.352 mmol)and Et₃N (0.1 mL, 0.732 mmol) and 2-pyridyl acetic acid hydrochloride(61 mg, 0.352 mmol). The resulting clear brown solution was stirred for2 hr at 50° C. Purification by preparative HPLC afforded racemicN-[5-({(1R,3S)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide(52 mg, 40%, Example 18 as a yellow powder. ¹H NMR (400 MHz, DMSO-d₆) δppm 12.50 (br s, 2H), 8.49 (d, J=4.03 Hz, 1H), 7.77 (td, J=7.70, 1.83Hz, 1H), 7.39 (d, J=7.82 Hz, 1H), 7.28 (dd, J=7.03, 5.32 Hz, 1H), 4.00(s, 2H) 3.43-3.58 (m, 1H), 3.06 (d, J=1.00 Hz, 2H), 2.37-2.48 (m, 1H),2.25-2.35 (m, 1H), 2.05-2.21 (m, 4H), 1.80-1.96 (m, 2H), 1.44-1.62 (m,2H). m/z (APCl+) for C₁₉H₂₁N₇O₂S₂ 444.1 (M+H)⁺.

40 mg was subjected to chiral separation by SFC to afford bothenantiomers. The analytical chiral separation by SFC was performed usinga Chiralpak OJ-H column (4.6 mm×250 mm column, 5 micron particle size),which was eluted with 30% MeOH in CO₂ held at 120 bar. A flow rate of 3mL/min gave Rt_((Peak 1))=3.47 minutes and Rt_((Peak 2))=4.72 minutes.

Example 17 (Peak 1): 16.78 mg, >99% ee (−). ¹H NMR (400 MHz, DMSO-d₆) δppm 12.50 (br s, 2H), 8.49 (d, J=4.03 Hz, 1H), 7.77 (td, J=7.70, 1.83Hz, 1H), 7.39 (d, J=7.82 Hz, 1H), 7.28 (dd, J=7.03, 5.32 Hz, 1H), 4.00(s, 2H) 3.43-3.58 (m, 1H), 3.06 (d, J=1.00 Hz, 2H), 2.37-2.48 (m, 1H),2.25-2.35 (m, 1H), 2.05-2.21 (m, 4H), 1.80-1.96 (m, 2H), 1.44-1.62 (m,2H). m/z (APCl+) for C₁₉H₂₁N₇O₂S₂ 444.1 (M+H)⁺.

Example 19 (Peak 2): 16.86 mg, 99% ee (+). ¹H NMR (400 MHz, DMSO-d₆) δppm 12.50 (br s, 2H), 8.49 (d, J=4.03 Hz, 1H), 7.77 (td, J=7.70, 1.83Hz, 1H), 7.39 (d, J=7.82 Hz, 1H), 7.28 (dd, J=7.03, 5.32 Hz, 1H), 4.00(s, 2H), 3.43-3.58 (m, 1H), 3.06 (d, J=1.00 Hz, 2H), 2.37-2.48 (m, 1H),2.25-2.35 (m, 1H), 2.05-2.21 (m, 4H), 1.80-1.96 (m, 2H), 1.44-1.62 (m,2H). m/z (APCl+) for C₁₉H₂₁N₇O₂S₂ 444.1 (M+H)⁺.

Example 20 (Scheme D): Preparation ofN-{5-[(1R,3S)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide

Step 1: Preparation of methyl2-((cis)-3-(5-(2-pyrimidin-4-yl)acetamino)-1,3,4-thiadiazol-2-yl)cyclopentyl)acetate

To a mixture ofmethyl-[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]acetate (241mg, 1.0 mmol) and HATU (480 mg, 1.2 mmol) in CH₂Cl₂ (20 mL) was addedEt₃N (0.28 mL, 2.0 mmol) at room temperature. Then, the resultingmixture was treated with 2-(pyrimidine-4-yl) acetic acid (152 mg, 1.1mmol), and it was stirred for 2 hr at room temperature. The resultingorange solution was diluted with water and CH₂Cl₂. The organic layer wasseparated, washed with brine, dried over Na₂SO₄ and evaporated to give ayellow solid. Purification via flash chromatography with a gradient of0%-30% MeOH in CH₂Cl₂ afforded the title compound (185 mg, 51% yield) asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.16 (s, 1H), 8.69 (d,J=5.29 Hz, 1H), 7.47 (d, J=5.04 Hz, 1H), 4.22 (s, 2H), 3.62 (s, 3H),3.47-3.56 (m, 1H), 2.34-2.48 (m, 4H), 2.11-2.26 (m, 1H), 1.79-2.05 (m,2H), 1.38-1.58 (m, 2H). m/z (APCl+) for C₁₆H₁₉N₅O₃S 362.2 (M+H)⁺.

Step 2: Preparation of2-((cis)-3-(5-(2-pyrimidin-4-yl)acetamino)-1,3,4-thiadiazol-2yl)cyclopentyl)aceticAcid

Methyl-2-((cis)-3-(5-(2-pyrimidin-4-yl)acetamino)-1,3,4-thiadiazol-2-yl)-cyclopentyl)acetate(1.27 g, 3.52 mmol) was dissolved in a mixture of MeOH (20 mL) and water(10 mL). Then, LiOH (674 mg, 28.2 mmol) was added to the methyl ester atroom temperature, and stirred for 2 hr. The reaction mixture wasevaporated to remove MeOH and the resulting mixture was diluted withwater. Then, the crude was washed with EtOAc and the aq. layer wasacidified with 1 N HCl to pH 3. The resulting solid was filtered off,washed with water and dried under vacuum to yield2-((cis)-3-(5-(2-pyrimidin-4-yl)acetamino)-1,3,4-thiadiazol-2yl)cyclopentyl)aceticacid as a yellow solid (238 mg, 19.5%). m/z (APCl+) for C₁₅H₁₇N₅O₃S348.2 (M+H)⁺.

Step 3: Preparation ofN-(5-((cis)-3-(2-(2-carbamothioylhydrazinyl)-2-oxoethyl)cyclopentyl)-1,3,4-thiadiazol-2yl)-2-(pyrimidin-4-yl)acetamide

To a mixture of2-((cis)-3-(5-(2-pyrimidin-4-yl)acetamino)-1,3,4-thiadiazol-2yl)cyclopentyl)aceticacid (238 mg, 0.69 mmol) and HATU (412 mg, 1.03 mmol) in DMF (3 mL) wasadded Et₃N (0.19 mL, 1.37 mmol) at room temperature. After 30 min, theresulting mixture was treated with thiosemicarbazide (96 mg, 1.03 mmol)and stirred for 3 hr at room temperature. Then, the reaction mixture wasevaporated under vacuum to remove DMF. The crude was diluted with CH₂Cl₂and the resulting solid was filtered off. The title compound wasimmediately transferred to a flask to be utilized in the dehydrationstep (step 4). m/z (APCl+) for C₁₆H₂₀N₈O₂S₂ 421.05 (M+H)⁺.

Step 4: Preparation ofN-(5-((cis)-3-((5-amino-1,3,4-thiadiazol-2-yl)-methyl)cyclopentyl)-1,3,4-thiadiazol-2-yl)-2-(pyrimidin-4-yl)acetamide

N-(5-((cis)-3-(2-(2-carbamothioylhydrazinyl)-2-oxoethyl)cyclopentyl)-1,3,4-thiadiazol-2yl)-2-(pyrimidin-4-yl)acetamidewas treated with neat sulfuric acid at 0° C. After 3 hr at 0° C., thereaction mixture was added dropwise to an ice-cold aq. NaHCO₃ solution.The resulting solid was filtered off, washed with water and dried undervacuum to giveN-(5-((cis)-3-((5-amino-1,3,4-thiadiazol-2-yl)methyl)cyclopentyl)-1,3,4-thiadiazol-2-yl)-2-(pyrimidin-4-yl)acetamide(118 mg, 38%) as a yellow solid. m/z (APCl+) for C₁₆H₁₈N₈OS₂ 403.2(M+H)⁺.

Step 5: Preparation ofN-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide(Example 20)

N-(5-((cis)-3-((5-amino-1,3,4-thiadiazol-2-yl)methyl)cyclopentyl)-1,3,4-thiadiazol-2-yl)-2-(pyrimidin-4-yl)acetamide(118 mg, 0.293 mmol) was dissolved in AcOH (1 mL) and treated with Ac₂O(56 μL, 0.586 mmol) at room temperature. After 30 min, the reactionmixture was purified by reverse phase chromatography eluting withMeCN:water (5:95 to 95:5) to give racemicN-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4-yl)acetamide as anorange solid (26 mg, 20%).

26 mg was subjected to chiral separation by SFC to afford bothenantiomers. The analytical chiral separation by SFC was performed usinga Chiralpak OJ-H column (4.6 mm×100 mm column, 5 micron particle size),which was eluted with 20% MeOH in CO₂ held at 120 bar. A flow rate of 4mL/min gave Rt_((Peak 1))=1.68 minutes and Rt_((Peak 2))=1.95 minutes.

Example 21 (Peak 1): 7.56 mg, >99% ee (−). ¹H NMR (600 MHz, DMSO-d₆) δppm 9.10 (d, J=2.9 Hz, 1H), 8.76 (dd, J=5.3, 2.2 Hz, 1H), 7.55 (t, J=3.8Hz, 1H), 4.03 (d, J=2.0 Hz, 2H), 3.50 (dq, J=10.4, 8.1 Hz, 1H), 3.06(dd, J=7.3, 2.5 Hz, 2H), 2.35-2.47 (m, 1H), 2.21-2.34 (m, 1H), 2.07-2.20(m, 4H), 1.77-1.95 (m, 2H), 1.43-1.60 (m, 2H). m/z (APCl+) forC₁₈H₂₀N₈O₂S₂ 445.2 (M+H)⁺.

Example 20 (Peak 2): 7.96 mg, 92% ee (+). ¹H NMR (600 MHz, DMSO-d₆) δppm 9.10 (d, J=2.9 Hz, 1H), 8.76 (dd, J=5.3, 2.2 Hz, 1H), 7.55 (t, J=3.8Hz, 1H), 4.03 (d, J=2.0 Hz, 2H), 3.50 (dq, J=10.4, 8.1 Hz, 1H), 3.06(dd, J=7.3, 2.5 Hz, 2H), 2.35-2.47 (m, 1H), 2.21-2.34 (m, 1H), 2.07-2.20(m, 4H), 1.77-1.95 (m, 2H), 1.43-1.60 (m, 2H). m/z (APCl+) forC₁₈H₂₀N₈O₂S₂ 445.2 (M+H)⁺.

Example 22 and Example 23 (Scheme E): Preparation of2-(pyridin-2-yl)-N-{5-[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide(Example 22) and2-(pyridin-2-yl)-N-{5-[(trans)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide(Example 23)

Step 1: Preparation of5-{[3-(5-amino-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-amine

3-(2-tert-butoxy-2-oxoethyl)cyclobutanecarboxylic acid (prepared as inWO2005019221 as mixture of cis to trans isomers 4:1) (2.3 g, 10.74 mmol)and thiosemicarbazide (2.17 g, 23.60 mmol) were suspended in POCl₃ (10mL) and heated to reflux for 1 hr, during which time, the suspensionbecame a clear yellow solution. The mixture was allowed to cool,evaporated in vacuo, and azeotoped three times with toluene to removePOCl₃ residues. The resulting amber oil was carefully quenched withsaturated NaHCO₃ solution (100 mL). The resulting suspension wasfiltered off and washed well with water and heptanes to give5-{[3-(5-amino-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-amine(1.34 g, 46%) as a tan powder as a 4:1 mixture of cis to trans isomers.m/z (APCl+) for C₉H₁₂N₆S₂ 269.05 (M+H)⁺.

Step 2: Preparation of2-(pyridin-2-yl)-N-{5-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide(Example 22) and2-(pyridin-2-yl)-N-{5-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide(Example 23)

To a solution of5-{[3-(5-amino-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-amine(200 mg, 7.45 mmol) in dry DMF (2 mL) was added HBTU (865 mg, 2.24mmol), Et₃N (0.42 mL, 2.98 mmol) and 2-pyridyl acetic acid hydrochloride(284 mg, 1.64 mmol). The resulting clear yellow solution was stirred for2 hr at 50° C. then purified by preparative HPLC to give a mixture ofcis- andtrans-2-(pyridin-2-yl)-N-{5-[3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide(113 mg, 30%) as a brown solid.

The cis and trans isomers were separated by SFC to afford bothdiastereomers. The analytical separation by SFC was performed using aChiralpak OJ-H column (4.6 mm×150 mm column, 5 micron particle size),which was eluted with 40% MeOH in CO₂ held at 120 bar. A flow rate of 4mL/min gave Rt_((Peak 1, Cis))=1.34 minutes andRt_((Peak 2, Trans))=1.72 minutes.

2-(pyridin-2-yl)-N-{5-[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide(Example 22) >99% de (61.5 mg, 54%) as a cream powder. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.65 (br s, 2H), 8.49 (d, J=4.28 Hz, 2H), 7.77 (t,J=7.52 Hz, 2H), 7.39 (d, J=7.70 Hz, 2H), 7.24-7.32 (m, 2H), 4.00 (s,4H), 3.74 (s, 1H), 3.12 (d, J=7.34 Hz, 2H), 2.69 (br s, 1H), 2.52-2.61(m, 2H), 2.06 (d, J=10.88 Hz, 2H). m/z (APCl+) for C₂₃H₂₂N₈O₂S₂ 507.1(M+H)⁺

2-(pyridin-2-yl)-N-{5-[(trans)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide(Example 23) 98% de (12.3 mg, 11%) as a cream powder. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.66 (br s, 2H), 8.49 (d, J=4.03 Hz, 2H), 7.76 (t,J=7.03 Hz, 2H), 7.39 (d, J=7.70 Hz, 2H), 7.20-7.34 (m, 2H), 3.87-4.08(m, 5H), 3.23 (d, J=7.58 Hz, 2H), 2.73-2.88 (m, 1H), 2.37-2.45 (m, 2H),2.21-2.34 (m, 2H). m/z (APCl+) for C₂₃H₂₂N₈O₂S₂ 507.1 (M+H)⁺

Example 24 (Scheme F): Preparation ofN-[5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide

Step 1: Preparation of methyl{3-[(cis)-5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate

3-(2-methoxy-2-oxoethyl)-cyclopentanecarboxylic acid (500 mg, 2.68 mmol)and 4-ethyl-3-thiosemicarbazide (320 mg, 2.68 mmol) were suspended inPOCl₃ (8 mL) and heated to reflux for 40 min, after which time thesuspension became a clear yellow solution. The mixture was allowed tocool, evaporated in vacuo, and then azeotoped three times with tolueneto remove POCl₃ residues. The resulting amber oil was carefully quenchedwith saturated NaHCO₃ solution (100 mL), and then extracted into EtOAc(3×50 mL). The combined organic extracts were dried over magnesiumsulfate, and evaporated to a give methyl{3-[(cis)-5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate. (325mg, 45%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.68 (s,3H) 3.29-3.47 (m, 3H) 2.33-2.48 (m, 4H) 2.10-2.24 (m, 1H) 1.81-2.07 (m,2H) 1.40-1.56 (m, 2H) 1.32 (t, J=7.21 Hz, 3H). m/z (APCl+) forC₁₂H₁₉N₃O₂S 270.1 (M+H)⁺.

Step 2: Preparation of{(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic Acid

To a solution of methyl{3-[(cis)-5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetate (325mg, 1.21 mmol) in MeOH (10 mL) was added 3 M LiOH solution (0.81 mL,2.41 mmol). The solution was stirred at room temperature overnight,concentrated to remove the MeOH then acidified to pH 4 with 1 M AcOH.The resulting solution was extracted with EtOAc (3×10 mL) followed byCH₂Cl₂:MeOH (95:5, 10 mL). The combined organic layers were dried overNa₂SO₄, filtered, and evaporated under vacuum to yield{(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid(289 mg, 94%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.33-3.51(m, 3H), 2.40-2.61 (m, 3H), 2.15-2.29 (m, 1H), 1.98-2.11 (m, 1H), 1.93(dd, J=8.74, 4.83 Hz, 1H), 1.47-1.63 (m, 2H), 1.41 (t, 3H). m/z (APCl+)for C₁₁H₁₇N₃O₂S 256.1 (M+H)⁺.

Step 3: Preparation of5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-N-ethyl-1,3,4-thiadiazol-2-amine

{(Cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}acetic acid(289 mg, 1.13 mmol) and thiosemicarbazide (104 mg, 1.13 mmol) weresuspended in POCl₃(10 mL) and heated to reflux for 1 hr, after whichtime the suspension became a clear yellow solution. The mixture wasallowed to cool, evaporated in vacuo, and then azeotoped three timeswith toluene to remove POCl₃ residues. The resulting amber oil wasslowly added to ice cold water (100 mL) and basified with 0.88 Nammonia. The resulting oil was extracted with EtOAc (3×40 mL) thenCH₂Cl₂:MeOH (95:5, 3×30 mL). The combined organics were dried overNa₂SO₄ and concentrated to give5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-N-ethyl-1,3,4-thiadiazol-2-amine(175 mg, 50%) as a cream solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.51 (t,J=5.07 Hz, 1H), 6.97 (s, 2H), 3.34 (m, J=9.80 Hz, 1H), 3.16-3.29 (m,2H), 2.81-2.93 (m, 2H), 2.15-2.47 (m, 2H), 2.03 (m, J=11.90, 7.20 Hz,1H), 1.70-1.90 (m, 2H), 1.34-1.52 (m, 2H), 1.14 (t, J=1.00 Hz, 3H). m/z(APCl+) for C₁₂H₁₈N₆S₂ 311.10 (M+H)⁺.

Step 4: PreparationN-[5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide

To a solution of5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-N-ethyl-1,3,4-thiadiazol-2-amine(88 mg, 0.28 mmol) in dry DMF (2 mL) was added HBTU (164 mg, 0.424mmol), Et₃N (0.08 mL, 0.566 mmol) and 2-pyridyl acetic acidhydrochloride (54 mg, 0.311 mmol). The resulting clear yellow solutionwas stirred for 2 hr at 50° C. then purified by preparative HPLC to givea solid which was slurried in heptanes, filtered and dried to giveN-[5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide(36 mg, 30%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.65 (br s, 1H), 8.47-8.52 (m, 1H), 7.77 (td, J=7.70, 1.83 Hz, 1H),7.50 (t, J=5.20 Hz, 1H), 7.39 (d, J=7.70 Hz, 1H), 7.28 (dd, J=6.60, 5.01Hz, 1H), 4.00 (s, 2H), 3.29 (m, 1H), 3.18-3.27 (m, 2H), 3.05 (d, J=7.34Hz, 2H), 2.31-2.45 (m, 1H), 2.15-2.27 (m, 1H), 1.98-2.11 (m, 1H),1.71-1.93 (m, 2H), 1.39-1.53 (m, 2H), 1.14 (t, J=7.15 Hz, 3H). m/z(APCl+) for C₁₉H₂₃N₇OS₂ 430.10 (M+H)⁺.

Example 25 (Scheme G): Preparation ofN,N′-(spiro[3.3]heptane-2,6-diyldipyridazine-6,3-diyl)bis[2-(pyridin-2-yl)acetamide]

Step 1: Preparation of 2,6-diiodospiro[3.3]heptanes

A solution of spiro[3.3]heptane-2,6-dicarboxylic acid (2.5 g, 11.0mmol), diiodohydantoin (11.4 g, 29.9 mmol) in 1,2-dichloroethane (136mL) under nitrogen was irradiated with a 500 W halogen lamp for 30 hr.The reaction was poured into saturated Na₂SO₃ (100 mL), and extractedwith CH₂Cl₂ (2×100 mL). The organic extracts were washed with saturatedNa₂SO₃ (100 mL), dried over Na₂SO₄, and concentrated. The residue waspurified by column chromatography over silica gel eluting with 0%-25%EtOAc in heptanes to provide 2,6-diiodospiro[3.3]heptanes (1.7 g, 36%)as a colorless solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.32 (quin, J=8 Hz,2H), 2.81-2.88 (m, 4H), 2.59-2.70 (m, 4H).

Step 2: Preparation ofN,N′-(spiro[3.3]heptane-2,6-diyldipyridazine-6,3-diyl)bis[2-(pyridin-2-yl)acetamide]

To a suspension of Zn dust (386 mg, 5.75 mmol) in dry degassed THF (0.58mL) was added 1,2-dibromoethane (26 μL, 0.21 mmol) under nitrogen. Then,the mixture was heated with a heat gun for about 30 sec until gasevolution was observed from the solution, indicating the activation ofZn. This process was repeated twice, before the mixture was allowed tocool to room temperature, followed by the addition of TMSCl (22 μL, 0.17mmol) and allowed to stir at room temperature for 5 min. A solution of2,6-diiodospiro[3.3]heptanes (500 mg, 1.44 mmol) in THF (1.4 mL) wasadded to the Zn solution, and then the resulting mixture was stirred at40° C. for 6 hr. After allowing the Zn to settle, the reaction mixturewas filtered through a syringe filter into a mixture ofN-(6-iodopyridazin-3-yl)-2-(pyridin-2-yl)-acetamide (489 mg, 1.44 mmol),Pd₂(dba)₃ (266 mg, 0.29 mmol), and tri(o-tolyl)phosphine (175 mg, 0.58mmol) in THF (5.2 mL). The reaction mixture was flushed with nitrogen,and stirred at 40° C. for 18 hr. The reaction mixture was cooled to roomtemperature, and quenched by addition of aq. NH₄Cl solution (containing10% NH₄OH). The mixture was stirred for 1 hr, extracted with CH₂Cl₂, andthe organic extracts dried over Na₂SO₄, filtered and concentrated. CrudeLCMS showed ca. 10% product formation. The material was purified byreverse phase HPLC to affordN′-(spiro[3.3]heptane-2,6-diyldipyridazine-6,3-diyl)bis[2-(pyridin-2-yl)acetamide](6.8 mg, 1%) as a colorless solid. ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.52(d, J=4 Hz, 2H), 8.37 (d, J=8 Hz, 2H), 7.81-7.84 (m, 2H), 7.61 (d, J=12Hz, 2H), 7.47 (d, J=8 Hz, 2H), 7.34-7.36 (m, 2H), 4.04 (s, 4H), 3.74(quin, J=8 Hz, 2H), 2.45-2.72 (m, 2H), 2.48-2.54 (m, 2H), 2.39-2.44 (m,2H), 2.33-2.39 (m, 2H). m/z (APCl+) for C₂₉H₂₈N₈O₂ 521.1 (M+H)⁺.

Example 26 (Scheme H): Preparation of2-(pyridin-2-yl)-N-{5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide

Step 1: Preparation ofN-[6-(3-oxocyclopent-1-en-1-yl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide

To a 100 mL pressure flask charged withN-(6-bromopyridazin-3-yl)-2-(pyridin-2-yl)-acetamide (5 g, 17.1 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one(10.7 g, 51.2 mmol), Pd(dppf)Cl₂ (1.39 g, 1.71 mmol), and CsF 13.0 g,85.4 mmol) was added THF (142 mL) and water (22.9 mL) under nitrogen.After 5 min at room temperature with stirring and nitrogen bubbling, thereaction vessel was placed in a pre-heated 100° C. sand bath behind ablast shield. After 18 hr, the mixture was cooled to room temperature,concentrated, diluted with 750 mL CH₂Cl₂ and allowed to stir for 15 min.The suspension was filtered through a plug of Celite® and concentrated.The residue was purified by silica gel chromatography eluting with 0-5%EtOH in EtOAc to provideN-[6-(3-oxocyclopent-1-en-1-yl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide(3.75 g, 75%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.69-8.72 (m,1H), 8.56 (d, J=8 Hz, 2H), 7.78-7.82 (m, 2H), 7.35-7.39 (m, 2H), 6.76(s, 1H), 4.08 (s, 2H), 3.27-3.29 (m, 2H), 2.62-2.65 (m, 2H). m/z (APCl+)for C₁₆H₁₄N₄O₂ 295.1 (M+H)⁺.

Step 2: Preparation ofN-[6-(3-oxocyclopentyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide

N-[6-(3-oxocyclopent-1-en-1-yl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide(1.5 g, 5.1 mmol) was placed in a 500 mL stainless steel Parr bomb andMeOH (255 mL) was added followed by Pd/C (E101, 10%, wet, 150 mg). Thereaction was stirred for 7 hr under 4 bar H₂ pressure. LCMS indicatedabout 50% conversion. A further portion of Pd/C (150 mg) was added, andthe reaction stirred for a further 18 hr at 50° C. under 6 bar H₂pressure. LCMS indicated complete conversion to the desired product withabout 10% over-reduction. The reaction was filtered through a plug ofCelite® and concentrated. The residue was purified by silica gelchromatography eluting with 0%-5% EtOH in EtOAc to provideN-[6-(3-oxocyclopentyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide (877mg, 58%) as a solid. ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.68-8.70 (m, 1H),8.44 (d, J=8 Hz, 1H), 7.75-7.79 (m, 1H), 7.27-7.39 (m, 3H), 4.06 (s,2H), 3.66-3.71 (m, 1H), 2.66-2.76 (m, 2H), 2.46-2.53 (m, 2H), 2.18-2.40(m, 2H). m/z (APCl+) for C₁₆H₁₆N₄O₂ 297.1 (M+H)⁺.

Step 3: Preparation ofN-{6-[(3E)-3-(cyanomethylidene)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide

To a suspension of NaH (65.8 mg, 60% suspension, 1.65 mmol) in THF (4.2mL) was added diethyl(cyanomethyl)phosphonate (292 mg, 1.65 mmol) in adrop-wise manner at 0° C. After being stirred for 10 min at roomtemperature, the solution was diluted with THF (5 mL), and thenN-[6-(3-oxocyclopentyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide (250mg, 0.84 mmol) was added in one portion. After 3 hr, the reaction wasclean and complete by LCMS and TLC. The reaction was quenched withsaturated aq. NH₄Cl and extracted with CH₂Cl₂. The organic layers werewashed with brine, dried over Na₂SO₄, and concentrated. The residue waspurified by silica gel chromatography eluting with 0%-5% EtOH in EtOActo provideN-{6-[(3E)-3-(cyanomethylidene)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide(245 mg, 91%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.30 (br s,1H), 8.48-8.50 (m, 1H), 8.22-8.24 (m, 1H), 7.74-7.76 (m, 1H), 7.63-7.76(m, 1H), 7.40-7.42 (m, 1H), 7.27-7.28 (m, 1H), 5.23-5.25 (m, 1H), 4.00(s, 2H), 3.52-3.56 (m, 1H), 2.65-2.91 (m, 4H), 2.23-2.27 (m, 1H),1.92-2.01 (m, 1H). m/z (APCl+) for C₁₈H₁₇N₅O 320.1 (M+H)⁺.

Step 4: Preparation ofN-{6-[3-(cyanomethyl)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide

To a stirred solution ofN-{6-[(3E)-3-(cyanomethylidene)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide(100 mg, 0.31 mmol) in THF (6.26 mL) at −78° C. was added L-Selectride(1.56 mL, 1 M in THF, 1.56 mmol), and the reaction was stirred at −78°C. for a further 4 hr. The reaction was quenched with saturated aq.NH₄Cl and allowed to warm to room temperature. The reaction wasextracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by silica gel chromatographyeluting with 0%-5% EtOH in EtOAc to provideN-{6-[3-(cyanomethyl)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide(85 mg, 91%) as a 1:1 mixture of cis and trans diastereomers, which wasused directly in the next step without further purification. ¹H NMR (400MHz, CDCl₃) δ ppm 8.61-8.63 (m, 1H), 8.29-8.32 (m, 1H), 7.55-7.65 (m,1H), 7.13-7.24 (m, 3H), 3.98 (s, 2H), 3.32-3.45 (m, 2H), 2.20-2.41 (m,4H), 1.64-2.01 (m, 5H). m/z (APCl+) for C₁₈H₁₉N₅O 322.1 (M+H)⁺.

Step 5: Preparation of2-(pyridin-2-yl)-N-{5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide

To a vial containingN-{6-[3-(cyanomethyl)cyclopentyl]pyridazin-3-yl}-2-(pyridin-2-yl)acetamide(80 mg, 0.25 mmol) and thiosemicarbazide (25 mg, 0.27 mmol) was addedtrifluoroacetic acid (250 μL). The resultant suspension was placed in apre-heated 70° C. sand bath at which time it became homogeneous. After 2hr, the reaction was about 80% complete. The reaction was allowed tostir for an additional 2 hr at 70° C., cooled to room temperature, andconcentrated. The residue was quenched with saturated aq. NaHCO₃, andextracted with CH₂Cl₂ to provide the crude material, which was purifiedby silica gel chromatography eluting with 0%-25% EtOH in EtOAc toprovide 27 mg of the intermediate aminothiadiazole, and 10 mg ofrecovered starting material. The aminothiadiazole was taken up in DMF(70 μL) and the 2-pyridylacetic acid hydrochloride (23 mg, 0.13 mmol)and pyridine (32.3 μL, 0.40 mmol) were added. To this mixture was addedT3P (86.3 μL, 50% in DMF, 0.15 mmol), and the reaction allowed to stirfor 2 hr at room temperature. LCMS indicated complete consumption of thestarting material. The pyridine was removed in vacuo, and the residuequenched with saturated aq. NaHCO₃. The mixture was extracted withCH₂Cl₂, and the extracts dried over Na₂SO₄, and concentrated. Theresidue was purified by silica gel chromatography eluting with 0%-5%EtOH in EtOAc to provide2-(pyridin-2-yl)-N-{5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide(60 mg) as a 1:1 mixture of cis and trans diastereomers. The compoundwas evaluated by a variety of purification methods, though no conditionscould be identified to separate any of the four isomers. Furtherpurification was carried out by reverse-phase HPLC to afford2-(pyridin-2-yl)-N-{5-[(3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide (3 mg, 2%) as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.63 (br s, 1H), 11.24 (d, J=4 Hz, 1H), 8.49(t, J=8 Hz, 2H), 8.18 (d, J=4 Hz, 1H), 7.76 (t, J=8 Hz, 2H), 7.57-7.61(m, 1H), 7.39 (d, J=8 Hz, 2H), 7.26-7.29 (m, 2H), 3.99 (s, 4H),3.46-3.50 (m, 1H), 3.29-3.39 (m, 1H), 3.05-3.10 (m, 2H), 1.75-2.24 (m,4H), 1.51-1.59 (m, 1H), 1.40-1.46 (m, 1H). m/z (APCl+) for C₂₈H₂₆N₈O₂S515.1 (M+H)⁺.

Preparation 1. Preparation of (cis)-3-(methoxycarbonyl)cyclopentaneCarboxylic Acid

To a suspension of cis-1,3-cyclopentanedicarboxylic anhydride (3.0 g, 21mmol) in MeOH (35 mL) was added sodium methoxide (1.2 g, 21 mmol)portionwise at room temperature. After 1 hr, the resulting clearsolution was evaporated, basified with 1 M NaOH and washed with EtOActwice. Then, the aq. layer was acidified with 1 N HCl to pH 2 andextracted with CH₂Cl₂ (3×25 mL). The combined organics were dried overNa₂SO₄ and evaporated to give (cis)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (2.7 g, 75%) as a clear oil. ¹H NMR (400MHz, CDCl₃) δ ppm 3.70 (s, 3H), 2.76-2.94 (m, 2H), 2.28 (dt, J=13.3, 8.0Hz, 1H), 2.15 (dt, J=13.3, 9.1 Hz, 1H), 1.89-2.07 (m, 4H). m/z (APCl+)for C₈H₁₂O₄ 173.2 (M+H)⁺.

Preparation 2. Preparation of methyl 3-bromopropiolate

To methyl propiolate (60 g, 713.6 mmol) dissolved in acetone (2 L) wasadded N-bromosuccinimide (147.22 g, 827.13 mmol), followed by silvernitrate (12.12 g, 71.37 mmol). A slight exotherm was observed with thereaction temperature increasing from 21-32° C. before the reactionmixture was left to stir at room temperature overnight. The resultinggrey suspension was evaporated to dryness in vacuo, pentane added (100mL) and filtered through Celite®, washing through with more pentane.This procedure was carried out twice more and then the combinedfiltrates evaporated in vacuo to give 113 g of methyl 3-bromopropiolate(98% yield) containing approximately 10% of starting material. ¹H NMR(400 MHz, CDCl₃) δ ppm 3.78 (s, 3H).

Preparation 3. Preparation of Methyl3-bromobicyclo[2.2.1]hepta-2,5-diene-2-carboxylate

Methyl 3-bromopropiolate (113 g, 698 mmol) and freshly crackedcyclopentadiene (92 g, 1.39 mol) were dissolved in toluene (570 mL) andheated to 90° C., under nitrogen for 2 hr. The reaction was cooled toroom temperature, and the toluene evaporated in vacuo to give a darkbrown oil. This was azeotroped three times with acetonitrile to removeexcess dicyclopentadiene, giving the title compound (119 g, 74% yield)as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.88-6.94 (m, 1H), 6.85(ddd, J=5.2, 3.1, 1.0 Hz, 1H), 4.00 (dqd, J=2.8, 1.7, 0.8 Hz, 1H), 3.76(s, 3H), 3.69 (ddtd, J=3.2, 2.4, 1.5, 0.7 Hz, 1H), 2.32 (dt, J=6.7, 1.7Hz, 1H), 2.13 (dt, J=6.7, 1.7 Hz, 1H).

Preparation 4. Preparation of Methyl3,3-dimethoxybicyclo[2.2.1]hept-5-ene-2-carboxylate

Methyl 3-bromobicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (119.0 g,519.5 mmol) was dissolved in MeOH (1 L) and sodium methoxide (289 mL ofa 30% solution in MeOH) added and the reaction was heated at reflux for45 min, and then saturated aq. NaHCO₃ (500 mL) was added, followed bywater (500 mL) and TBME (1 L). The TBME layer was separated and theaqueous layer extracted once more with TBME (1 L). The combined organicextracts were dried over MgSO₄ and evaporated in vacuo to give methyl3,3-dimethoxybicyclo[2.2.1]hept-5-ene-2-carboxylate as a yellow oil(75.0 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.60 (dd, J=5.7, 2.8 Hz,0.5H), 6.25 (dd, J=5.6, 3.0 Hz, 0.5H), 6.13-6.18 (m, 0.5H), 6.07 (dd,J=5.6, 3.1 Hz, 0.5H), 3.67 (d, J=18.5 Hz, 3H), 3.40 (s, 1.5H), 3.31 (s,1.5H), 3.24 (s, 1.5H), 3.17 (s, 1.5H), 3.06 (d, J=3.4 Hz, 0.5H),2.92-3.04 (m, 2H), 2.50 (d, J=2.7 Hz, 0.5H), 2.18 (ddt, J=9.0, 1.6, 0.9Hz, 0.5H), 1.67-1.73 (m, 0.5H), 1.63 (dq, J=9.1, 2.2 Hz, 1H).

Preparation 5. Preparation of Methyl3-oxobicyclo[2.2.1]hept-5-ene-2-carboxylate

Methyl 3,3-dimethoxybicyclo[2.2.1]hept-5-ene-2-carboxylate (75.0 g,353.37 mmol) was dissolved in THF (400 mL) and 2 M HCl (400 mL) added.The mixture was stirred at room temperature for 1 hr, then diluted withTBME (1000 mL) and the layers separated. The aq. layer was extractedonce more with TBME (1000 mL) and the combined organic extracts driedover MgSO₄ and evaporated in vacuo to give methyl3-oxobicyclo[2.2.1]hept-5-ene-2-carboxylate as a yellow oil (55.0 g,93%), as a mixture of diastereoisomers. ¹H NMR (400 MHz, CDCl₃) δ ppm6.77 (dd, J=5.4, 2.7 Hz, 1H), 6.03-6.09 (m, 1H), 3.72 (d, J=13.0 Hz,3H), 3.34 (dq, J=2.8, 1.4 Hz, 1H), 3.18-3.23 (m, 1H), 3.16 (dt, J=3.1,0.7 Hz, 1H), 2.14 (dddd, J=9.6, 2.4, 1.4, 0.6 Hz, 1H), 1.92 (dtd, J=9.1,1.5, 0.8 Hz, 1H).

Preparation 6. Preparation of(cis)-4-(2-methoxy-2-oxoethyl)cyclopent-2-enecarboxylic Acid

Methyl 3-oxobicyclo[2.2.1]hept-5-ene-2-carboxylate (55.21 g, 332.24mmol) was dissolved in dioxane (600 mL) and cooled to 0° C. After dropwise addition of NaOH (2 M, 149.51 mL, 299.02 mmol) over 30 min, thereaction was stirred for a further 30 min, before quenching with HCl (3M, 100 mL). The resulting mixture was extracted with EtOAc (2×500 mL).After drying of the organic layers over MgSO₄, the solvent was removedunder reduced pressure to give a brown oil purified by dry flash,eluting with neat CH₂Cl₂, followed by 10%, then 15% and 20% EtOAc inCH₂Cl₂. Evaporation of the appropriate fractions gave(cis)-4-(2-methoxy-2-oxoethyl)cyclopent-2-enecarboxylic acid (40.4 g,66%). ¹H NMR (400 MHz, CDCl₃) δ ppm 5.85 (dt, J=5.7, 2.3 Hz, 1H), 5.79(dt, J=5.6, 2.2 Hz, 1H), 3.68 (s, 3H), 3.60 (ddq, J=9.0, 6.9, 2.4 Hz,1H), 3.09-3.23 (m, 1H), 2.36-2.55 (m, 3H), 1.79 (dt, J=13.3, 6.5 Hz,1H).

Preparation 7. Preparation of (cis)-3-(2-methoxy-2 oxoethyl)cyclopentanecarboxylic Acid

(Cis)-methyl 3-oxobicyclo[2.2.1]heptane-2-carboxylate (40.4 g, 219.3mmol) was dissolved in EtOAc (400 mL), and 10% wt. Pd/C (2 g, 5% w/wrelative to substrate) was added. The mixture was then stirred at roomtemperature for 2 hrs, under an atmosphere of 50 psi hydrogen. Thecatalyst was then removed via filtration through a pad of Celite®, andthe filtrate evaporated, affording a pale yellow oil (41 g). ¹H NMRindicated trace impurities; heptane was added, and the suspensionfiltered and evaporated to give (cis)-3-(2-methoxy-2oxoethyl)cyclopentane carboxylic acid (31 g, 76% yield). ¹H NMR (400MHz, CDCl₃) δ ppm 3.67 (s, 3H), 2.85 (ddd, J=8.8, 7.5, 1.5 Hz, 1H),2.37-2.43 (m, 2H), 2.15-2.37 (m, 2H), 1.84-2.01 (m, 3H), 1.49 (dt,J=12.6, 9.4 Hz, 1H), 1.29-1.42 (m, 1H).

Preparation 8. Preparation of (cis)-3-(carboxymethyl)cyclopentaneCarboxylic Acid

(Cis)-3-(2-methoxy-2-oxoethyl)cyclopentanecarboxylic acid (10.6 g, 56.93mmol) was dissolved in 2 M NaOH (56.9 mL) and stirred at roomtemperature for 2 hr. The reaction was acidified with concentrated HClwith ice cooling to pH 4 and stirred at room temperature overnight toallow crystallization. The resulting solid was filtered off, washed wellwith water and dried at 60° C. under vacuum to give(cis)-3-(carboxymethyl)cyclopentanecarboxylic acid (6.70 g, 68%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.00 (s, 2H), 2.61-2.78(m, 1H), 2.21-2.28 (m, 2H), 2.10-2.21 (m, 1H), 2.02 (dt, J=12.4, 7.4 Hz,1H), 1.70-1.84 (m, 3H), 1.14-1.38 (m, 2H).

Alternate Preparation 8. Preparation of(cis)-3-(carboxymethyl)cyclopentane Carboxylic Acid

(Cis)-3-(2-methoxy-2-oxoethyl)cyclopentane carboxylic acid (10.6 g,56.93 mmol) was dissolved in 2 M NaOH (56.9 mL) and stirred at roomtemperature for 2 hr. The reaction was acidified with concentrated HClwith ice cooling to ca. pH 4 and stirred at room temperature overnightto allow crystallization. The resulting solid was filtered off, washedwell with water and dried at 60° C. under vacuum to give(cis)-3-(carboxymethyl)cyclopentanecarboxylic acid (6.70 g, 68%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.00 (s, 2H), 2.61-2.78(m, 1H), 2.21-2.28 (m, 2H), 2.10-2.21 (m, 1H), 2.02 (dt, J=12.4, 7.4 Hz,1H), 1.70-1.84 (m, 3H), 1.14-1.38 (m, 2H).

Preparation 9. Preparation of bicyclo[3.2.1]oct-2-ene

To a stirred solution of norbornene (120 g, 1.27 mol) and triethylbenzylammonium chloride (900 mg, 3.95 mmol) in CHCl₃ (129 mL) was added 50%aq. NaOH (130 mL). The resulting solution was stirred at roomtemperature for 3 days. Water (130 mL) was added and the reactionfiltered. The precipitate was washed with CH₂Cl₂ (ca. 500 mL), and thecombined organic layers washed with brine (2×300 mL), dried over Na₂SO₄,and concentrated to give crude product, which was purified bydistillization to give 3,4-dichlorobicyclo[3.2.1]oct-2-ene (123 g, 54%)as a yellow oil.

To a well-stirred solvent of liquid NH₃ (ca. 500 mL) was added Na (24 g,1.04 mol) in portions over a period of 40 min at ca. −65° C. After beingstirred for ca. 20 min, a solution of3,4-dichlorobicyclo[3.2.1]oct-2-ene (20 g, 0.11 mol) in t-BuOH (20 mL)and THF (20 mL) was added in a drop-wise manner. During addition, alarge amount of precipitate was formed. The reaction mixture was stirredat ca. −65° C. for a further ca. 3 hr. TLC (petroleum ether, detected byI₂) showed the reaction was complete. The reaction mixture was warmed toca. 35° C., solid NH₄Cl (30 g) was added slowly, and the reactionstirred for 20 min. The resulting mixture was poured into a 5 L beaker,water (300 mL) was added slowly, and the mixture stirred for 20 min. Thereaction flask was carefully washed with EtOH to quench residual sodium.The mixture was extracted with CH₂Cl₂ (2×500 mL), the organic layer waswashed with water (200 mL), dried over Na₂SO₄, and concentrated in vacuoat ca. 25° C. to give bicyclo[3.2.1]oct-2-ene (8 g, 80% pure, bpt ˜138C, 66%), as a pale yellow oil, which was used without furtherpurification (for references on the synthesis of the olefin, and analternative route that has been employed from 4-vinylcyclohex-1-ene, seeTetrahedron Lett., 2004, 45, 9447 and Tetrahedron Lett., 1976, 16,1257).

Preparation 10. Preparation of (1 S,3R)-3-(carboxymethyl)cyclopentaneCarboxylic Acid

To a well-stirred mixture of bicyclo[3.2.1]oct-2-ene (25 g, 231 mmol)and RuCl₃.H₂O (1.04 g, 4.62 mmol) in MeCN (250 mL), EtOAc (250 mL) andwater (350 mL) was added NaIO₄ (295 g, 231 mmol) at room temperature inportions over a period of ca. 60 min. The resulting mixture was stirredat room temperature for ca. 16 hr. TLC (petroleum ether) indicated thereaction was complete. The reaction mixture was filtered and the cakewas washed with EtOAc (ca. 700 mL) and water (300 mL). The organic layerwas washed with brine (500 mL), dried over Na₂SO₄, filtered throughCelite® and concentrated in vacuo to afford a gummy residue (30 g). Theresidue was dissolved in water (ca. 200 mL) and basified to pH ˜10 with2 M aq. NaOH. The aqueous solution was washed with EtOAc (400 mL),acidified to pH ˜4 and then extracted with EtOAc (2×500 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated underhigh vacuum to give racemic (cis)-3-(carboxymethyl)cyclopentanecarboxylic acid (26 g, >90% purity, 65%) as a pale brown solid, whichwas subjected to chiral SFC separation.

A 105 g batch of racemic diacid was subjected to chiral separation bySFC using an Chiralcel AD-3 3 μm column (4.6×100 mm) eluting with 10%MeOH @ 120 bar with a flow rate of 4 mL/min.

(1R,3S)-3-(carboxymethyl)cyclopentanecarboxylic acid (49.2 g) wasobtained as a white solid as peak 1 (R_(t)=1.45 min, >99% ee); [α]²²_(D)=−7.1° (c=1.0, MeOH). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.00 (s, 2H),2.61-2.78 (m, 1H), 2.21-2.28 (m, 2H), 2.10-2.21 (m, 1H), 2.02 (dt,J=12.4, 7.4 Hz, 1H), 1.70-1.84 (m, 3H), 1.14-1.38 (m, 2H).

(1 S,3R)-3-(carboxymethyl)cyclopentane carboxylic acid (49 g) wasobtained as a white solid as peak 2 (R_(t)=2.33 min, >99% ee); [α]²²_(D)=+7.1° (c=1.0, MeOH). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.00 (s, 2H),2.61-2.78 (m, 1H), 2.21-2.28 (m, 2 H), 2.10-2.21 (m, 1H), 2.02 (dt,J=12.4, 7.4 Hz, 1H), 1.70-1.84 (m, 3H), 1.14-1.38 (m, 2H).

The following examples were made with non-critical changes orsubstitutions to the exemplified procedures that would be understood toone skilled in the art.

TABLE 1 Chiral LRMS Separation Example No. (Scheme) m/z ConditionsStructure and Compound Name [M + H]⁺ ¹H NMR (SFC)

  (Scheme A) (rac)-2-phenyl-N-{6-[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclopentyl)methyl]pyridazin-3-yl}acetamide 1 514.1 (400 MHz, DMSO- d₆) δ ppm 12.63 (br s, 1 H), 11.22(s, 1 H), 8.49 (d, J = 4.78 Hz, 1 H), 8.19 (d, J = 9.06 Hz, 1 H), 7.76(td, J = 7.68, 1.76 Hz, 1 H), 7.56 (d, J = 9.32 Hz, 1 H), 7.19-7.43 (m,7 H), 3.99 (s, 2 H), 3.76 (s, 2 H), 3.44- 3.55 (m, 1 H), 2.94 (d, J =7.30 Hz, 2 H), 2.03-2.28 (m, 3 H), 1.74-1.91 (m, 2 H), 1.42-1.60 (m, 2H). Racemic Cis

  (Scheme B) 2* 521.1 (400 MHz, DMSO- d₆) δ ppm 12.65 (br s, 2 H), 8.49(d, J = 4.77 Hz, 2 H), 7.77 (td, J = 7.6, 1.9 Hz, 2 H), 7.39 (d, J = 7.8Hz, 2 H), 7.28 (ddd, J = 7.6, 4.9, 1.2 Hz, 2 H), 4.00 (s, 4 H), 3.50(dt, J = 10.3, 7.7 Hz, 1 H), 3.07 (d, J = 7.3 Hz, 2 H), 2.35-2.47 (m, 1H), 2.29 (dt, J = 13.5, 7.1 Hz, 1 H), 2.12 (dtd, J = 15.9, 8.9, 7.7, 3.8Hz, 1 H), 1.76-1.96 (m, 2 H), 1.44-1.61 (m, 2 H). Rt (Peak 2) = 1.98minutes Chiralpak OJ-H 4.6 x 100 mm column 30% MeOH (w 0.1% DEA) @ 120bar CO₂, 4 mL/min. 2-(pyridin-2-yl)-N-(5-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)acetamide

  (Scheme B) 3 521.1 (400 MHz, DMSO- d₆) δ ppm 12.68 (s, 2 H), 8.45-8.52(m, 2 H), 7.77 (td, J = 7.6, 1.9 Hz, 2 H), 7.39 (d, J = 7.8 Hz, 2 H),7.28 (ddd, J = 7.6, 4.9, 1.2 Hz, 2 H), 4.00 (s, 4 H), 3.50 (dt, J =10.3, 7.7 Hz, 1 H), 3.07 (d, J = 7.3 Hz, 2 H), 2.35-2.47 (m, 1 H), 2.29(dt, J = 13.5, 7.1 Hz, 1 H), 2.12 (dtd, J = 15.9, 8.9, 7.7, 3.8 Hz, 1H), 1.76-1.96 (m, 2 H), 1.40-1.63 (m, 2 H). Racemic Cis(rac)-2-(pyridin-2-yl)-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)acetamide

  (Scheme B) 4* 521.1 (400 MHz, DMSO- d₆) δ ppm 12.68 (s, 2 H),8.45-8.52 (m, 2 H), 7.77 (td, J = 7.6, 1.9 Hz, 2 H), 7.39 (d, J = 7.8Hz, 2 H), 7.28 (ddd, J = 7.6, 4.9, 1.2 Hz, 2 H), 4.00 (s, 4 H), 3.50(dt, J = 10.3, 7.7 Hz, 1 H), 3.07 (d, J = 7.3 Hz, 2 H), 2.35-2.47 (m, 1H), 2.29 (dt, J = 13.5, 7.1 Hz, 1 H), 2.12 (dtd, J = 15.9, 8.9, 7.7, 3.8Hz, 1 H), 1.76-1.96 (m, 2 H), 1.40-1.63 (m, 2 H). Rt (Peak 1) = 1.60minutes Chiralpak OJ-H 4.6 x 100 mm column 30% MeOH (w 0.1% DEA) @ 120bar CO₂, 4 mL/min. 2-(pyridin-2-yl)-N-(5-{[(1S,3R)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)acetamide

  (Scheme B) 5 367.1 (400 MHz, DMSO- d₆) δ ppm 12.38 (s, 2 H), 3.57 (m,1 H), 3.07 (d, J = 7.4 Hz, 2 H), 2.42 (dq, J = 9.8, 7.6 Hz, 1 H), 2.29(dt, J = 13.4, 7.0 Hz, 1 H), 2.16 (d, J = 1.2 Hz, 6 H), 2.09-2.14 (m, 1H), 1.78-1.95 (m, 2 H), 1.43-1.62 (m, 2 H). Rt (Peak 1) = 3.30 minutesChiralpak AS-H 4.6 x 250 mm column 30% MeOH (w. 0.1% DEA) @ 140 bar CO₂,3 mL/min. N-[5-({(1R,3S)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4- thiadiazol-2-yl]acetamide

  (Scheme B) 6** 367.1 (400 MHz, DMSO- d₆) δ ppm 12.38 (s, 2 H), 3.57(m, 1 H), 3.07 (d, J = 7.4 Hz, 2 H), 2.42 (dq, J = 9.8, 7.6 Hz, 1 H),2.29 (dt, J = 13.4, 7.0 Hz, 1 H), 2.16 (d, J = 1.2 Hz, 6 H), 2.09-2.14(m, 1 H), 1.78-1.95 (m, 2 H), 1.43-1.62 (m, 2 H). Racemic Cis(rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide

  (Scheme B) 7 367.1 (400 MHz, DMSO- d₆) δ ppm 12.38 (s, 2 H), 3.57 (m,1 H), 3.07 (d, J = 7.4 Hz, 2 H), 2.42 (dq, J = 9.8, 7.6 Hz, 1 H), 2.29(dt, J = 13.4, 7.0 Hz, 1 H), 2.16 (d, J = 1.2 Hz, 6 H), 2.09-2.14 (m, 1H), 1.78-1.95 (m, 2H), 1.43-1.62 (m, 2 H). Rt (Peak 2) = 4.62 minutesChiralpak AS-H 4.6 x 250 mm column 30% MeOH (w. 0.1% DEA) @ 140 bar CO₂,3 mL/min. N-[5-({(1S,3R)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4- thiadiazol-2-yl]acetamide

8 519.2 (400 MHz, DMSO- d₆) δ ppm 12.66 (s, 2 H), 6.72-7.88 (m, 10 H),3.78 (d, J = 1.5 Hz, 4 H), 3.49 (dd, J = 10.0, 7.5 Hz, 1 H), 3.05 (d, J= 7.3 Hz, 2 H), 2.34- 2.47 (m, 1 H), 2.26 (dt, J = 13.0, 6.9 Hz, 1 H),2.03-2.17 (m, 1 H), 1.76-1.93 (m, 2 H), 1.41-1.60 (m, 2 H). Rt (Peak 1)= 8.51 minutes Chiralpak AS-H 4.6 x 250 mm column 40% MeOH (w. 0.1% DEA)@ 140 bar CO₂, 3 mL/min. (Scheme B) 2-phenyl-N-(5-{[(1R,3S)-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)acetamide

9 519.2 (400 MHz, DMSO- d₆) δ ppm 12.66 (s, 2 H), 6.72-7.88 (m, 10 H),3.78 (d, J = 1.5 Hz, 4 H), 3.49 (dd, J = 10.0, 7.5 Hz, 1 H), 3.05 (d, J= 7.3 Hz, 2 H), 2.34- 2.47 (m, 1 H), 2.26 (dt, J = 13.0, 6.9 Hz, 1 H),2.03-2.17 (m, 1 H), 1.76-1.93 (m, 2 H), 1.41-1.60 (m, 2 H). Racemic Cis(Scheme B) (rac)-2-phenyl-N-(5-{[(cis)-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)acetamide

10 519.2 (400 MHz, DMSO- d₆) δ ppm 12.66 (s, 2 H), 6.72-7.88 (m, 10 H),3.78 (d, J = 1.5 Hz, 4 H), 3.49 (dd, J = 10.0, 7.5 Hz, 1 H), 3.05 (d, J= 7.3 Hz, 2 H), 2.34- 2.47 (m, 1 H), 2.26 (dt, J = 13.0, 6.9 Hz, 1 H),2.03-2.17 (m, 1 H), 1.76-1.93 (m, 2 H), 1.41-1.60 (m, 2 H). Rt (Peak 2)= 10.20 minutes Chiralpak AS-H 4.6 x 250 mm column 40% MeOH (w. 0.1%DEA) @ 140 bar CO₂, 3 mL/min. (Scheme B) 2-phenyl-N-(5-{[(1S,3R)-3-{5-[(phenylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)acetamide

  (Scheme C) (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]benzamide 11** 429.1 (400 MHz, DMSO- d₆) δ ppm12.89 (br s, 1 H), 12.35 (br s, 1 H), 8.10 (d, J = 7.46 Hz, 2 H), 7.62-7.71 (m, 1 H), 7.50- 7.60 (m, 2 H), 3.45- 3.61 (m, 1 H), 3.12 (d, J =7.09 Hz, 2 H), 2.27-2.40 (m, 1 H), 2.07-2.24 (m, 4 Racemic Cis H),1.81-2.02 (m, 2 H), 1.48-1.69 (m, 2 H).

  (Scheme C) N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4- thiadiazol-2-yl]benzamide 12*429.1 (400 MHz, DMSO- d₆) δ ppm 12.89 (br s, 1 H), 12.35 (br s, 1 H),8.10 (d, J = 7.46 Hz, 2 H), 7.62- 7.71 (m, 1 H), 7.50- 7.60 (m, 2 H),3.45- 3.61 (m, 1 H), 3.12 (d, J = 7.09 Hz, 2 H), 2.27-2.40 (m, 1 H),2.07-2.24 (m, 4 Rt (Peak 1) = 4.63 minutes Chiralpak OJ-H 4.6 x 250 mmcolumn 30% MeOH @ 140 bar CO₂, 3 mL/min. H), 1.81-2.02 (m, 2 H),1.48-1.69 (m, 2 H).

  (Scheme C) N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4- thiadiazol-2-yl]benzamide 13*429.1 (400 MHz, DMSO- d₆) δ ppm 12.89 (br s, 1 H), 12.35 (br s, 1 H),8.10 (d, J = 7.46 Hz, 2 H), 7.62- 7.71 (m, 1 H), 7.50- 7.60 (m, 2 H),3.45- 3.61 (m, 1 H), 3.12 (d, J = 7.09 Hz, 2 H), 2.27-2.40 (m, 1 H),2.07-2.24 (m, 4 Rt (Peak 2) = 5.57 minutes Chiralpak OJ-H 4.6 x 250 mmcolumn 30% MeOH @ 140 bar CO₂, 3 mL/min. H), 1.81-2.02 (m, 2 H),1.48-1.69 (m, 2 H).

  (Scheme C) N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide 14* 443.0 (600 MHz, DMSO- d₆) δ ppm7.22- 7.38 (m, 3 H), 3.79 (s, 2 H), 3.45-3.55 (m, 1 H), 3.06 (d, J =7.46 Hz, 2 H), 2.36- 2.47 (m, 1 H), 2.28 (d, J = 12.15 Hz, 1 H). Rt(Peak 2) = 7.67 minutes Chiralpak OJ-H 4.6 x 250 mm column 40% MeOH (w.0.1% DEA) @ 140 bar CO₂, 3 mL/min.

  (Scheme C) (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide 15 443.0 (600 MHz, DMSO- d₆) δppm 7.22- 7.38 (m, 3 H), 3.79 (s, 2 H), 3.45-3.55 (m, 1 H), 3.06 (d, J =7.46 Hz, 2 H), 2.36- 2.47 (m, 1 H), 2.28 (d, J = 12.15 Hz, 1 H). RacemicCis

  (Scheme C) N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-phenylacetamide 16* 443.0 (600 MHz, DMSO- d₆) δ ppm7.22- 7.38 (m, 3 H), 3.79 (s, 2 H), 3.45-3.55 (m, 1 H), 3.06 (d, J =7.46 Hz, 2 H), 2.36- 2.47 (m, 1 H), 2.28 (d, J = 12.15 Hz, 1 H). Rt(Peak 1) = 4.54 minutes Chiralpak OJ-H 4.6 x 250 mm column 40% MeOH (w.0.1% DEA) @ 140 bar CO₂, 3 mL/min.

  (Scheme C) N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide 17* 443.1 (600 MHz, DMSO- d₆)δ ppm 8.49 (d, J = 4.68 Hz, 1 H), 7.71-7.79 (m, 1 H), 7.39 (d, J = 7.76Hz, 1 H), 7.28 (dd, J = 7.02, 5.12 Hz, 1 H), 4.00 (s, 2 H), 3.44- 3.57(m, 1 H), 3.07 (d, J = 7.32 Hz, 2 H), 2.41 (m, 1 H), 2.24-2.34 (m, 1 H),2.06-2.19 (m, 4 H), 1.80-1.96 (m, 2 H), 1.55 (m, J = 12.15 Hz, 2 H). Rt(Peak 2) = 4.72 minutes Chiralpak OJ-H 4.6 x 250 mm column 30% MeOH (w.0.1% DEA) @ 140 bar CO₂, 3 mL/min.

  (Scheme C) (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2- yl)acetamide 18 443.1 (600 MHz,DMSO- d₆) δ ppm 8.49 (d, J = 4.68 Hz, 1 H), 7.71-7.79 (m, 1 H), 7.39 (d,J = 7.76 Hz, 1 H), 7.28 (dd, J = 7.02, 5.12 Hz, 1 H), 4.00 (s, 2 H),3.44- 3.57 (m, 1 H), 3.07 (d, J = 7.32 Hz, 2 H), 2.41 (m, 1 H),2.24-2.34 (m, 1 H), 2.06-2.19 (m, 4 H), 1.80-1.96 (m, 2 H), 1.55 (m, J =12.15 Hz, 2 H). Racemic Cis

  (Scheme C) N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide 19* 443.1 (600 MHz, DMSO- d₆)δ ppm 8.49 (d, J = 4.68 Hz, 1 H), 7.71-7.79 (m, 1 H), 7.39 (d, J = 7.76Hz, 1 H), 7.28 (dd, J = 7.02, 5.12 Hz, 1 H), 4.00 (s, 2 H), 3.44- 3.57(m, 1 H), 3.07 (d, J = 7.32 Hz, 2 H), 2.41 (m, 1 H), 2.24-2.34 (m, 1 H),2.06-2.19 (m, 4 H), 1.80-1.96 (m, 2 H), 1.55 (m, J = 12.15 Hz, 2 H). Rt(Peak 1) = 3.47 minutes Chiralpak OJ-H 4.6 x 250 mm column 30% MeOH (w.0.1% DEA) @ 140 bar CO₂, 3 mL/min.

  (Scheme D) N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4- yl)acetamide 20* 445.2 (600 MHz, DMSO-d₆) δ ppm 9.10 (d, J = 2.9 Hz, 1 H), 8.76 (dd, J = 5.3, 2.2 Hz, 1 H),7.55 (t, J = 3.8 Hz, 1 H), 4.03 (d, J = 2.0 Hz, 2 H), 3.50 (dq, J =10.4, 8.1 Hz, 1 H), 3.06 (dd, J = 7.3, 2.5 Hz, 2 H), 2.47-2.35 (m, 1 H),2.21-2.34 (m, 1 H), Rt (Peak 2) = 1.95 minutes Chiralcel OJ-H 4.6 x 100mm column 20% MeOH @ 120 bar CO₂, 4 mL/min. 2.07-2.20 (m, 4 H),1.77-1.95 (m, 2 H), 1.43-1.60 (m, 2 H).

  (Scheme D) N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-4- yl)acetamide 21* 445.2 (600 MHz, DMSO-d₆) δ ppm 9.10 (d, J = 2.9 Hz, 1 H), 8.76 (dd, J = 5.3, 2.2 Hz, 1 H),7.55 (t, J = 3.8 Hz, 1 H), 4.03 (d, J = 2.0 Hz, 2 H), 3.50 (dq, J =10.4, 8.1 Hz, 1 H), 3.06 (dd, J = 7.3, 2.5 Hz, 2 H), 2.47-2.35 (m, 1 H),2.21-2.34 (m, 1 H), Rt (Peak 1) = 1.68 minutes Chiralcel OJ-H 4.6 x 100mm column 20% MeOH @ 120 bar CO₂, 4 mL/min. 2.07-2.20 (m, 4 H),1.77-1.95 (m, 2 H), 1.43-1.60 (m, 2 H).

  (Scheme E) 2-(pyridin-2-yl)-N-{5-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2- yl}acetamide 22 507.1 (400MHz, DMSO- d₆) δ ppm 12.65 (br s, 2 H), 8.49 (d, J = 4.28 Hz, 2 H), 7.77(t, J = 7.52 Hz, 2 H), 7.39 (d, J = 7.70 Hz, 2 H), 7.24-7.32 (m, 2 H),4.00 (s, 4 H), 3.74 (s, 1 H), 3.12 (d, J = 7.34 Hz, 2 H), 2.69 (br s, 1H), 2.52-2.61 (m, 2 H), 2.06 (d, J = 10.88 Hz, 2 H). Rt (Peak 1) = 1.34minutes Chiralcel OJ-H 4.6 x 150 mm column 40% MeOH @ 120 bar CO₂, 4mL/min (dia- stereomer separation).

  (Scheme E) 2-(pyridin-2-yl)-N-{5-[(trans-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4- 23 507.1 (400 MHz, DMSO- d₆) δ ppm12.66 (br s, 2 H), 8.49 (d, J = 4.03 Hz, 2 H), 7.76 (t, J = 7.03 Hz, 2H), 7.39 (d, J = 7.70 Hz, 2 H), 7.20-7.34 (m, 2 H), 3.87-4.08 (m, 5 H),3.23 (d, J = 7.58 Hz, 2 H), 2.73- 2.88 (m, 1 H), 2.37- 2.45 (m, 2 H),2.21- 2.34 (m, 2 H). Rt (Peak 2) = 1.72 minutes Chiralcel OJ-H 4.6 x 150mm column 40% MeOH @ 120 bar CO₂, 4 mL/min (dia- stereomer separation).thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4- thiadiazol-2-yl}acetamide

  (Scheme F) (rac)-N-[5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2- yl)acetamide 24 430.1 (400 MHz,DMSO- d₆) δ ppm 12.65 (br s, 1 H), 8.47-8.52 (m, 1 H), 7.77 (td, J =7.70, 1.83 Hz, 1 H), 7.50 (t, J = 5.20 Hz, 1 H), 7.39 (d, J = 7.70 Hz, 1H), 7.28 (dd, J = 6.60, 5.01 Hz, 1 H), 4.00 (s, 2 H), 3.29 (m, 1 H),3.18-3.27 (m, 2 H), 3.05 (d, J = 7.34 Racemic Cis Hz, 2 H), 2.31- 2.45(m, 1 H), 2.15- 2.27 (m, 1 H), 1.98- 2.11 (m, 1 H), 1.71- 1.93 (m, 2 H),1.39- 1.53 (m, 2 H), 1.14 (t, J = 7.15 Hz, 3 H).

  (Scheme G) 25 521.1 (400 MHz, MeOD- d₄) δ ppm 8.52 (d, J = 4 Hz, 2 H),8.37 (d, J = 8 Hz, 2 H), 7.81-7.84 (m, 2 H), 7.61 (d, J = 12 Hz, 2 H),7.47 (d, J = 8 Hz, 2 H), 7.34- 7.36 (m, 2 H), 4.04 (s, 4 H), 3.74 (quin,J = 8 Hz, 2 H), 2.45- 2.72 (m, 2 H), 2.48- 2.54 (m, 2 H), 2.39- 2.44 (m,2 H), 2.33- 2.39 (m, 2 H). Racemic N,N′-(spiro[3.3]heptane-2,6-diyldipyridazine-6,3-diyl)bis[2-(pyridin-2- yl)acetamide]

  (Scheme G) 26 515.1 400 MHz, DMSO-d₆) δ ppm 12.63 (br s, 1 H), 11.24(d, J = 4 Hz, 1 H), 8.49 (t, J = 8 Hz, 2 H), 8.18 (d, J = 4 Hz, 1 H),7.76 (t, J = 8 Hz, 2 H), 7.57-7.61 (m, 1 H), 7.39 (d, J = 8 Hz, 2 H),7.26-7.29 (m, 2 H), 3.99 (s, 4 H), 3.46-3.50 (m, 1 H), 3.29-3.39 (m, 1H), 3.05-3.10 (m, 2 H), 1.75-2.24 (m, 4 H), 1.51-1.59 (m, 1 H),1.40-1.46 (m, 1 H). 1:1 mix of racemic cis/trans dia- stereomers2-(pyridin-2-yl)-N-{5-[(3-{6-[(pyridin-2- ylacetyl)amino]pyridazin-3-yl}cyclopentyl)methyl]-1,3,4-thiadiazol-2- yl}acetamide

27 451.2 (400 MHz, DMSO- d₆) δ ppm 12.06 (s, 2 H), 3.46-3.57 (m, 1 H),3.07 (d, J = 7.3 Hz, 2 H), 2.36- 2.47 (m, 1 H), 2.30 (dt, J = 13.5, 6.9Hz, 1 H), 2.05-2.19 (m, 1 H), 1.80-1.98 (m, 2 H), 1.55 (dt, J = 19.9,9.9 Hz, 2 H), 1.21-1.27 (m, 18 H). Racemic Cis (Scheme B)(rac)-N-(5-{[(cis)-3-{5-[(2,2- dimethylpropanoyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)-2,2-dimethylpropanamide

28* 451.2 (400 MHz, DMSO- d₆) δ ppm 12.06 (s, 2 H), 3.46-3.57 (m, 1 H),3.07 (d, J = 7.3 Hz, 2 H), 2.36- 2.47 (m, 1 H), 2.30 (dt, J = 13.5, 6.9Hz, 1 H), 2.05-2.19 (m, 1 H), 1.80-1.98 (m, 2 H), 1.55 (dt, J = 19.9,9.9 Hz, 2 H), 1.21-1.27 (m, 18 H). Rt (Peak 1) = 1.93 minutes ChiralpakAS-H 4.6 x 250 mm column 20% MeOH (w. 0.1% DEA) @ 140 bar CO₂, 3 mL/min.(Scheme B) N-(5-{[(cis)-3-{5-[(2,2- dimethylpropanoyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)-2,2-dimethylpropanamide

29* 451.2 (400 MHz, DMSO- d₆) δ ppm 12.06 (s, 2 H), 3.46-3.57 (m, 1 H),3.07 (d, J = 7.3 Hz, 2 H), 2.36- 2.47 (m, 1 H), 2.30 (dt, J = 13.5, 6.9Hz, 1 H), 2.05-2.19 (m, 1 H), 1.80-1.98 (m, 2 H), 1.55 (dt, J = 19.9,9.9 Hz, 2 H), 1.21-1.27 (m, 18 H). Rt (Peak 2) = 2.51 minutes ChiralpakAS-H 4.6 x 250 mm column 20% MeOH (w. 0.1% DEA) @ 140 bar CO₂, 3 mL/min.(Scheme B) N-(5-{[(cis)-3-{5-[(2,2- dimethylpropanoyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)-2,2-dimethylpropanamide

  (Scheme B) 30 549.2 (400 MHz, MeOH- d₄) δ ppm 8.56 (s, 2 H), 8.46 (dt,J = 5.0, 1.4 Hz, 2 H), 7.87- 7.96 (m, 2 H), 7.44 (dd, J = 8.0, 4.9 Hz, 2H), 4.02 (qd, J = 7.1, 3.8 Hz, 2 H), 3.49-3.63 (m, 1 H), 3.13 (d, J =7.3 Hz, 2 H), 2.45-2.58 (m, 1 H), 2.40 (dt, J = 13.6, 6.9 Hz, 1 H), 2.22(dt, J = 13.0, 7.6 Hz, 1 H), 1.89- 2.05 (m, 2 H), 1.58 (m, 8 H). RacemicCis (rac)-2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)propanamide

31* 549.2 (700 MHz, DMSO- d₆) δ ppm 8.51 (br s, 2 H), 8.42 (dd, 2 H),7.76 (m, 2 H), 7.38 (d, J = 2.56 Hz, 2 H), 4.02 (m, 1 H), 3.45 (m, 1 H),3.00 (m, 2 H), 2.36 (m, 1 H), 2.23 (m, 1 H), 2.08 (br s, 1 H), 1.69-1.92 (m, 3 H), 1.45 (br s, 6 H), 1.04- 1.25 (m, 2 H). Rt (Peak 1) =15.42 minutes Chiralpak OJ-H 4.6 x 250 mm column 10% MeOH (w. 0.1% DEA)@ 140 bar CO₂, 3 mL/min. (Scheme B)2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)propanamide

32* 549.2 (700 MHz, DMSO- d₆) δ ppm 8.49- 8.53 (m, 2 H), 8.40- 8.44 (m,2 H), 7.72- 7.78 (m, 2 H), 7.36- 7.41 (m, 2 H), 3.98- 4.07 (m, 2 H),3.43- 3.50 (m, 1 H) 2.98- 3.06 (d, 2 H), 2.33- 2.42 (m, 1 H), 2.18- 2.28(m, 1 H), 2.05- 2.12 (m, 1 H), 1.71- 1.87 (m, 2 H), 1.45 (m, 8 H). Rt(Peak 2) = 17.45 minutes Chiralpak OJ-H 4.6 x 250 mm column 10% MeOH (w.0.1% DEA) @ 140 bar CO₂, 3 mL/min. (Scheme B)2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)propanamide

  (Scheme B) 33* 549.2 (400 MHz, MeOH- d₄) δ ppm 8.56 (s, 2 H), 8.46(dt, J = 5.0, 1.4 Hz, 2 H), 7.87- 7.96 (m, 2 H), 7.44 (dd, J = 8.0, 4.9Hz, 2 H), 4.02 (qd, J = 7.1, 3.8 Hz, 2 H), 3.49-3.63 (m, 1 H), 3.13 (d,J = 7.3 Hz, 2 H), 2.45-2.58 (m, 1 H), 2.40 (dt, J = 13.6, 6.9 Hz, 1 H),2.22 (dt, J = 13.0, 7.6 Hz, 1 H), 1.89- 2.05 (m, 2 H), 1.58 (m, 8 H). Rt(Peak 4) = 19.02 minutes Chiralpak OJ-H 4.6 x 250 mm column 10% MeOH (w.0.1% DEA) @ 140 bar CO₂, 3 mL/min.2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1 ,3,4- thiadiazol-2-yl)propanamide

34* 549.2 (700 MHz, DMSO- d₆) δ ppm 8.51- 8.58 (m, 2 H), 8.44 (dd, J =2.90 Hz, 2 H), 7.77 (m, 2 H), 7.29-7.48 (m, 2 H), 4.03 (m, 2 H), 3.46(m, 1 H), 3.03 (d, J = 7.00 Hz, 2 H), 2.37 (m, 1 H), 2.24 (m, J = 11.61,6.15 Hz, 1 H), 2.09 (m, J = 4.78 Hz, 1 H), 1.75- 1.91 (m, 2 H), 1.41-1.58 (m, 8 H). Rt (Peak 3) = 18.15 minutes Chiralpak OJ-H 4.6 x 250 mmcolumn 10% MeOH (w. 0.1% DEA) @ 140 bar CO₂, 3 mL/min. (Scheme B)2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)propanamide

  (Scheme B) 35* 549.2 (700 MHz, DMSO- d₆) δ ppm 8.51 (br s, 2 H), 8.42(dd, J = 4.70, 1.28 Hz, 2 H), 7.75 (ddt, J = 7.90, 3.93, 1.94, 1.94 Hz,2 H), 7.38 (dd, J = 7.86, 4.78 Hz, 2 H), 3.96-4.12 (m, 2 H), 3.42-3.50(m, 1 H), 3.01 (d, J = 7.34 Hz, 2 H), 2.32-2.42 (m, 1 H), 2.19-2.27 (m,1 H), 2.02-2.14 (m, 1 H), 1.72-1.86 (m, 2 H), 1.39-1.52 (m, 8 H). Rt(Peak 6) = 23.19 minutes Chiralpak OJ-H 4.6 x 250 mm column 10% MeOH (w.0.1% DEA) @ 140 bar CO₂, 3 mL/min.2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)propanamide

  (Scheme B) 36* 549.2 (700 MHz, DMSO- d₆) δ ppm 8.51 (br. s., 2H), 8.42(dd, J = 4.70, 1.28 Hz, 2H), 7.75 (dddd, J = 7.86, 4.27, 2.05, 1.88 Hz,2H), 7.38 (dd, J = 7.86, 4.78 Hz, 2H), 3.96-4.07 (m, 2H), 3.40-3.54 (m,1H), 3.01 (d, J = 7.34 Hz, 2H), 2.32-2.42 (m, 1H), 2.20-2.29 (m, 1H),2.07 (dd, J = 12.73, 6.23 Hz, 1H), 1.73-1.91 (m, 2H) 1.39-1.54 (m, 8H).Rt (Peak 7) = 24.41 minutes Chiralpak OJ-H 4.6 x 250 mm column 10% MeOH(w. 0.1% DEA) @ 140 bar CO₂, 3 mL/min.2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)propanamide

  (Scheme B) 37* 549.2 (700 MHz, DMSO- d₆) δ ppm 8.50 (d, J = 2.22 Hz, 2H), 8.39-8.45 (m, 2 H), 7.75 (td, J = 3.89, 2.14 Hz, 2 H), 7.33- 7.45(m, 2 H), 3.95- 4.04 (m, 2 H), 3.45 (d, J = 7.86 Hz, 1 H), 2.95-3.07 (m,2 H), 2.32-2.42 (m, 1 H), 2.19-2.29 (m, 1 H), 2.04-2.15 (m, 1 H),1.74-1.94 (m, 2 H), 1.38-1.54 (m, 8 H). Rt (Peak 5) = 22.05 minutesChiralpak OJ-H 4.6 x 250 mm column 10% MeOH (w. 0.1% DEA) @ 140 bar CO₂,3 mL/min. 2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- thiadiazol-2-yl)propanamide

  (Scheme B) 2-(pyridin-3-yl)-N-(5-{[(cis)-3-(5-{[2-(pyridin-3-yl)propanoyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- 38* 549.2 (700 MHz, DMSO- d₆)δ ppm 8.51 (br s, 2 H), 8.42 (dd, J = 4.78, 1.37 Hz, 2 H), 7.75 (ddt, J= 8.01, 4.04, 1.92, 1.92 Hz, 2 H), 7.38 (dd, J = 7.86, 4.78 Hz, 2 H),3.98-4.04 (m, 2 H), 3.45 (dd, J = 9.82, 7.60 Hz, 1 H), 3.01 (d, J = 7.34Hz, 2 H), 2.36 (dd, J = 9.31, 7.60 Hz, 1 H), 2.22 (dd, J = 12.73, 6.75Hz, 1 H), 2.08 (dd, J = 12.81, 6.32 Hz, 1 H), 1.72- 1.89 (m, 2 H), 1.40-1.52 (m, 8 H). Rt (Peak 8) = 30.41 minutes Chiralpak OJ-H 4.6 x 250 mmcolumn 10% MeOH (w. 0.1% DEA) @ 140 bar CO₂, 3 mL/min.thiadiazol-2-yl)propanamide

  (Scheme B) 39 283.2 (400 MHz, DMSO- d₆) δ ppm 7.00 (s, 4 H), 3.34-3.27(m, 1 H), 2.85 (d, J = 7.2 Hz, 2 H), 2.13- 2.38 (m, 2 H), 2.10- 1.94 (m,1 H), 1.72- 1.89 (m, 2 H), 1.32- 1.52 (m, 2 H). Racemic Cis(rac)-5-{[(cis)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4- thiadiazol-2-amine

  (Scheme B) 40 283.2 (400 MHz, DMSO- d₆) δ ppm 7.00 (s, 4 H), 3.34-3.27(m, 1 H), 2.85 (d, J = 7.2 Hz, 2 H), 2.13- 2.38 (m, 2 H), 2.10- 1.94 (m,1 H), 1.72- 1.89 (m, 2 H), 1.32- 1.52 (m, 2 H). Rt (Peak 1) = 2.01minutes Chiralpak AS-H 4.6 x 100 mm column 40% MeOH @ 140 bar CO₂, 4mL/min. 5-{[(1R,3S)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol- 2-amine

  (Scheme B) 41 283.2 (400 MHz, DMSO- d₆) δ ppm 7.00 (s, 4 H), 3.34-3.27(m, 1 H), 2.85 (d, J = 7.2 Hz, 2 H), 2.13- 2.38 (m, 2 H), 2.10- 1.94 (m,1 H), 1.72- 1.89 (m, 2 H), 1.32- 1.52 (m, 2 H). Rt (Peak 2) = 5.27minutes Chiralpak AS-H 4.6 x 100 mm column 40% MeOH @ 140 bar CO₂, 4mL/min. 5-{[(1S,3R)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}-1,3,4-thiadiazol- 2-amine

  (Scheme C) 42 325.1 (400 MHz, DMSO- d₆) δ ppm 6.96 (s, 2 H), 3.47-3.53(m, 1 H), 2.88 (d, J = 7.30 Hz, 2 H), 2.23- 2.39 (m, 2 H), 2.06- 2.16(m, 4 H), 1.79- 1.94 (m, 2 H), 1.42- 1.58 (m, 2 H). Racemic Cis(rac)-N-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4- thiadiazol-2-yl)acetamide

  (Scheme D) (rac)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide 43 443.0 (600 MHz, DMSO- d₆) δppm 7.30- 7.33 (m, 4 H), 7.26 (td, J = 6.11, 2.71 Hz, 1 H), 3.79 (s, 2H), 3.50 (dd, J = 9.95, 7.46 Hz, 1 H), 3.05 (d, J = 7.46 Hz, 2 H), 2.41(dd, J = 9.44, 7.39 Hz, 1 H), 2.24-2.31 (m, 1 H), 2.15 (s, 3 H), 2.07-Racemic Cis 2.13 (m, 1 H), 1.80- 1.92 (m, 2 H), 1.45- 1.58 (m, 2 H).

  (Scheme D) N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide 44* 443.0 (600 MHz, DMSO- d₆) δ ppm7.30- 7.33 (m, 4 H), 7.26 (td, J = 6.11, 2.71 Hz, 1 H), 3.79 (s, 2 H),3.50 (dd, J = 9.95, 7.46 Hz, 1 H), 3.05 (d, J = 7.46 Hz, 2 H), 2.41 (dd,J = 9.44, 7.39 Hz, 1 H), 2.24-2.31 (m, 1 H), 2.15 (s, 3 H), 2.07- Rt(Peak 1) = 2.78 minutes Chiralpak AS-H 4.6 x 250 mm column 40% MeOH @140 bar CO₂, 3 mL/min. 2.13 (m, 1 H), 1.80- 1.92 (m, 2 H), 1.45- 1.58(m, 2 H).

  (Scheme D) N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-phenylacetamide 45* 443.0 (600 MHz, DMSO- d₆) δ ppm7.30- 7.33 (m, 4 H), 7.26 (td, J = 6.11, 2.71 Hz, 1 H), 3.79 (s, 2 H),3.50 (dd, J = 9.95, 7.46 Hz, 1 H), 3.05 (d, J = 7.46 Hz, 2 H), 2.41 (dd,J = 9.44, 7.39 Hz, 1 H), 2.24-2.31 (m, 1 H), 2.15 (s, 3 H), 2.07- Rt(Peak 2) = 3.69 minutes Chiralpak AS-H 4.6 x 250 mm column 40% MeOH @140 bar CO₂, 3 mL/min. 2.13 (m, 1 H), 1.80- 1.92 (m, 2 H), 1.45- 1.58(m, 2 H).

  (Scheme C) 46 444.1 (400 MHz, DMSO- d₆) δ ppm 8.77 (d, J = 5.04 Hz, 2H), 7.39-7.45 (m, 1 H), 4.14 (s, 2 H), 3.46- 3.56 (m, 1 H), 3.04- 3.11(m, 2 H), 2.39- 2.48 (m, 1 H), 2.24- 2.36 (m, 1 H), 2.08- 2.20 (m, 4 H),1.81- 1.95 (m, 2 H), 1.46- 1.64 (m, 2 H). Racemic Cis(rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-2- yl)acetamide

  (Scheme C) (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrazin-2- 47 444.1 (400 MHz, DMSO- d₆) δ ppm12.37 (br s, 2 H), 8.67 (d, J = 1.35 Hz, 1 H), 8.58 (d, J = 1.47 Hz, 1H), 8.53-8.57 (m, 1 H), 4.08 (s, 2 H), 3.43-3.57 (m, 1 H), 3.07 (d, J =7.34 Hz, 2 H), 2.38-2.47 (m, 1 H), 2.24-2.35 (m, 1 H), 2.06-2.18 (m, 4H), 1.80-1.94 (m, 2 H), 1.44-1.62 (m, 2 H). Racemic Cis yl)acetamide

  (Scheme D) (rac)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}benzamide 48 429.0 (400 MHz, DMSO- d₆) δ 8.10 (dd,J = 7.1, 1.8 Hz, 2 H), 7.52 (dt, J = 28.5, 7.3 Hz, 3 H), 3.44- 3.58 (m,1 H), 3.08 (d, J = 7.3 Hz, 2 H), 2.37-2.48 (m, 1 H), 2.23-2.36 (m, 1 H),2.16 (s, 3 H), 2.05- Racemic Cis 2.14 (m, 1 H), 1.76- 1.97 (m, 2 H),1.42- 1.67 (m, 2 H).

  (Scheme C) 49 445.1 (600 MHz, DMSO- d₆) δ ppm 9.09 (s, 1 H), 8.74 (s,2 H), 3.92 (s, 2 H), 3.49 (m, 1 H), 3.06(d, J = 7.17 Hz, 2 H), 2.36-2.46 (m, 1 H), 2.23- 2.33 (m, 1 H), 2.07- 2.22 (m, 4 H), 1.79- 1.93(m, 2H), 1.42- 1.62 (m, 2 H). Racemic Cis(rac)-N-[(cis)-5-({3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5- yl)acetamide

  (Scheme C) 50* 445.1 (600 MHz, DMSO- d₆) δ ppm 9.09 (s, 1 H), 8.74 (s,2 H), 3.92 (s, 2 H), 3.49 (m, 1 H), 3.06 (d, J = 7.17 Hz, 2 H), 2.36-2.46 (m, 1 H), 2.23- 2.33 (m, 1 H), 2.07- 2.22 (m, 4 H), 1.79- 1.93 (m,2 H), 1.42- 1.62 (m, 2 H). Rt (Peak 1) = 2.60 minutes Chiralcel OJ-H 4.6x 250 mm column 30% MeOH @ 140 bar CO₂, 3 mL/min.N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5- yl)acetamide

  (Scheme C) 51* 445.1 (600 MHz, DMSO- d₆) δ ppm 9.09 (s, 1 H), 8.74 (s,2 H), 3.92 (s, 2 H), 3.49 (m, 1 H), 3.06 (d, J = 7.17 Hz, 2 H), 2.36-2.46 (m, 1 H), 2.23- 2.33 (m, 1 H), 2.07- 2.22 (m, 4 H), 1.79- 1.93 (m,2 H), 1.42- 1.62 (m, 2 H). Rt (Peak 2) = 3.36 minutes Chiralcel OJ-H 4.6x 250 mm column 30% MeOH @ 140 bar CO₂, 3 mL/min.N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyrimidin-5- yl)acetamide

  (Scheme C) (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin- 52 458.1 (600 MHz, DMSO- d₆)δ ppm 8.36 (s, 1 H), 7.60 (dd, J = 7.90, 2.05 Hz, 1 H), 7.21 (d, J =8.05 Hz, 1 H), 3.79 (s, 2 H), 3.48 (m, J = 7.90 Hz, 1 H), 3.05 (d, J =7.32 Hz, 2 H), 2.43 (s, 3 H), 2.40 (m, 1 H), 2.24-2.31 (m, 1 H), 2.15(s, 3 H), 2.12 (m, 1 H), 1.80-1.92 (m, 2 H), 1.45-1.59 (m, 2 H). RacemicCis 3-yl)acetamide

  (Scheme C) N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin-3- 53* 458.1 (600 MHz, DMSO- d₆) δppm 8.36 (s, 1 H), 7.60 (dd, J = 7.90, 2.05 Hz, 1 H), 7.21 (d, J = 8.05Hz, 1 H), 3.79 (s, 2 H), 3.48 (m, J = 7.90 Hz, 1 H), 3.05 (d, J = 7.32Hz, 2 H), 2.43 (s, 3 H), 2.40 (m, 1 H), 2.24-2.31 (m, 1 H), 2.15 (s, 3H), 2.12 (m, 1 H), 1.80-1.92 (m, 2 H), 1.45-1.59 (m, 2 H). Rt (Peak 2) =8.27 minutes Chiralcel OJ-H 4.6 x 250 mm column 15% MeOH @ 140 bar CO₂,3 mL/min. yl)acetamide

  (Scheme C) N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(6-methylpyridin-3- 54* 458.1 (600 MHz, DMSO- d₆) δppm 8.36 (s, 1 H), 7.60 (dd, J = 7.90, 2.05 Hz, 1 H), 7.21 (d, J = 8.05Hz, 1 H), 3.79 (s, 2 H), 3.48 (m, J = 7.90 Hz, 1 H), 3.05 (d, J = 7.32Hz, 2 H), 2.43 (s, 3 H), 2.40 (m, 1 H), 2.24-2.31 (m, 1 H), 2.15 (s, 3H), 2.12 (m, 1 H), 1.80-1.92 (m, 2 H), 1.45-1.59 (m, 2 H). Rt (Peak 1) =6.64 minutes Chiralcel OJ-H 4.6 x 250 mm column 15% MeOH @ 140 bar CO₂,3 mL/min. yl)acetamide

  (Scheme D) (rac)-N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2- yl)acetamide 55 444.0 (400 MHz,DMSO- d₆) δ ppm 8.48 (d, J = 4.28 Hz, 1 H), 7.75 (d, J = 1.51 Hz, 1 H),7.38 (d, J = 7.81 Hz, 1 H), 7.26 (dd, J = 7.05, 5.29 Hz, 1 H), 3.95 (s,2 H), 3.50 (d, J = 9.32 Hz, 1 H), 3.05 (d, J = 7.30 Hz, 2 H), 2.36-2.46(m, 1 H), 2.28 (d, J = 12.34 Racemic Cis Hz, 1 H), 2.15 (s, 4 H),1.80-1.94 (m, 2 H), 1.43-1.62 (m, 2 H).

  (Scheme D) N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide 56* 444.0 (400 MHz, DMSO- d₆)δ ppm 8.48 (d, J = 4.28 Hz, 1 H), 7.75 (d, J = 1.51 Hz, 1 H), 7.38 (d, J= 7.81 Hz, 1 H), 7.26 (dd, J = 7.05, 5.29 Hz, 1 H), 3.95 (s, 2 H), 3.50(d, J = 9.32 Hz, 1 H), 3.05 (d, J = 7.30 Hz, 2 H), 2.36-2.46 (m, 1 H),Rt (Peak 1) = 5.14 minutes Chiralpak AS-H 4.6 x 250 mm column 30% MeOH @140 bar CO₂, 3 mL/min. 2.28 (d, J = 12.34 Hz, 1 H), 2.15 (s, 4 H),1.80-1.94 (m, 2 H), 1.43-1.62 (m, 2 H).

  (Scheme D) N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide 57* 444.0 (400 MHz, DMSO- d₆)δ ppm 8.48 (d, J = 4.28 Hz, 1 H), 7.75 (d, J = 1.51 Hz, 1 H), 7.38 (d, J= 7.81 Hz, 1 H), 7.26 (dd, J = 7.05, 5.29 Hz, 1 H), 3.95 (s, 2 H), 3.50(d, J = 9.32 Hz, 1 H), 3.05 (d, J = 7.30 Hz, 2 H), 2.36-2.46 (m, 1 H),Rt (Peak 2) = 6.82 minutes Chiralpak AS-H 4.6 x 250 mm column 30% MeOH @140 bar CO₂, 3 mL/min. 2.28 (d, J = 12.34 Hz, 1 H), 2.15 (s, 4 H),1.80-1.94 (m, 2 H), 1.43-1.62 (m, 2 H).

  (Scheme D) N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-5- yl)acetamide 58* 445.0 (700 MHz, DMSO-d₆) δ ppm 9.09 (s, 1 H), 8.74 (s, 2 H), 3.91 (s, 2 H), 3.50 (dq, J =10.4, 8.1 Hz, 1 H), 3.05 (d, J = 7.3 Hz, 2 H), 2.42 (dq, J = 10.0, 7.5Hz, 1 H), 2.28 (dt, J = 13.6, 7.1 Hz, 1 H), 2.16 (s, 3 H), 2.08- 2.13(m, 1 H), 1.80- Rt (Peak 2) = 6.06 minutes Chiralcel OJ-H 4.6 x 250 mmcolumn 20% MeOH @ 140 bar CO₂, 3 mL/min. 1.92 (m, 2 H), 1.44- 1.58 (m, 2H).

  (Scheme D) N-{5-[(cis)-3-{[5-(acetylamino)-1,3,4-thiadiazol-2-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyrimidin-5- yl)acetamide 59* 445.0 (700 MHz, DMSO-d₆) δ ppm 9.09 (s, 1 H), 8.74 (s, 2 H), 3.91 (s, 2 H), 3.50 (dq, J =10.4, 8.1 Hz, 1 H), 3.05 (d, J = 7.3 Hz, 2 H), 2.42 (dq, J = 10.0, 7.5Hz, 1 H), 2.28 (dt, J = 13.6, 7.1 Hz, 1 H), 2.16 (s, 3 H), 2.08- 2.13(m, 1 H), 1.80- Rt (Peak 1) = 5.03 minutes Chiralcel OJ-H 4.6 x 250 mmcolumn 20% MeOH @ 140 bar CO₂, 3 mL/min. 1.92 (m, 2 H), 1.44- 1.58 (m, 2H).

  (Scheme B) N,N′-{[-1,2,2-trimethylcyclopentane-1,3-diyl]di-1,3,4-thiadiazole-5,2- 60 395.1 (400 MHz, DMSO- d₆) δ ppm 12.40(s, 2 H), 3.77 (t, J = 9.72 Hz, 1 H), 2.85- 2.97 (m, 1 H), 2.39- 2.47(m, 1 H), 2.31 (d, J = 10.51 Hz, 1 H), 2.17 (s, 6 H) 1.83-1.94 (m, 1 H),1.46 (s, 3 H), 1.22 (s, 3 H), 0.38 (s, 3 H). Racemic diyl}diacetamide

  (Scheme B) 61 533.0 (400 MHz, DMSO- d₆) δ ppm 12.67 (br s, 2 H), 8.49(d, J = 4.28 Hz, 2 H), 7.77 (t, J = 7.58 Hz, 2 H), 7.40 (d, J = 7.70 Hz,2 H), 7.25-7.32 (m, 2 H), 4.01 (s, 4 H) 3.78 (quin, J = 8.38 Hz, 2 H),2.62- 2.71 (m, 2 H), 2.37- 2.47 (m, 4 H), 2.25- 2.34 (m, 2 H). RacemicN,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2- yl)acetamide]

  (Scheme E) N-[5-({cis-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)-1,3,4- 62 352.4 (400 MHz, DMSO- d₆) δppm 12.36 (br s, 2 H), 3.67-3.81 (m, 1 H), 3.12 (d, J = 6.97 Hz, 2 H),2.63- 2.77 (m, 1 H), 2.55 (d, J = 8.56 Hz, 2 H), 2.16 (s, 6 H), 2.07 (m,J = 9.40 Hz, 2 H). Rt (Peak 1) = 2.61 minutes Chiralpak OJ-H 4.6 x 250mm column 10% MeOH @ 140 bar CO₂, 3 mL/min (dia- stereomer separation).thiadiazol-2-yl]acetamide

  (Scheme E) N-[5-({trans-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclobutyl}methyl)-1,3,4- thiadiazol-2-yl]acetamide 63352.4 (400 MHz, DMSO- d₆) δ ppm 12.38 (br s, 2 H), 3.95 (t, J = 6.91 Hz,1 H), 3.23 (d, J = 7.70 Hz, 2 H), 2.73-2.88 (m, 1 H), 2.38-2.48 (m, 2H), 2.24-2.35 (m, 2 H), 2.16 (s, 6 H). Rt (Peak 2) = 3.25 minutesChiralpak OJ-H 4.6 x 250 mm column 10% MeOH (w. 0.1% DEA) @ 140 bar CO₂,3 mL/min (dia- stereomer separation).

  (Scheme D) N-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol- 64* 401.0 (400 MHz, MeOH- d₄)δ ppm 7.30- 7.38 (m, 5 H), 3.83 (s, 2 H), 3.52 (m, 1 H), 2.99 (d, J =6.8 Hz, 2 H), 2.43- 2.45 (m, 2 H), 2.23- 2.30 (m, 1 H), 1.98- 2.05 (m, 2H), 1.61- 1.63 (m, 2 H), 1.31- 1.39 (m, 2 H). Rt (Peak 1) = 4.85 minutesChiralpak AS-H 4.6 x 250 mm column 40% MeOH @ 140 bar CO₂, 3 mL/min.2-yl)-2-phenylacetamide

  (Scheme D) N-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol- 2-yl)-2-phenylacetamide 65*401.0 (400 MHz, MeOH- d₄) δ ppm 7.30- 7.38 (m, 5 H), 3.83 (s, 2 H), 3.52(m, 1 H), 2.99 (d, J = 6.8 Hz, 2 H), 2.43- 2.45 (m, 2 H), 2.23- 2.30 (m,1 H), 1.98- 2.05 (m, 2 H), 1.61- 1.63 (m, 2 H), 1.31- 1.39 (m, 2 H). Rt(Peak 2) = 5.73 minutes Chiralpak AS-H 4.6 x 250 mm column 40% MeOH @140 bar CO₂, 3 mL/min.

  (Scheme F) (rac)-N-[5-({(cis)-3-[5-(ethylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]acetamide 66 353.1 (400 MHz, DMSO- d₆) δ ppm 12.66(s, 2 H), 6.72-7.88 (m, 10 H), 3.78 (d, J = 1.5 Hz, 4 H), 3.49 (dd, J =10.0, 7.5 Hz, 1 H), 3.05 (d, J = 7.3 Hz, 2 H), 2.34- 2.47 (m, 1 H), 2.26(dt, J = 13.0, 6.9 Hz, Racemic Cis 1 H), 2.03-2.17 (m, 1 H), 1.93-1.76(m, 2 H), 1.41-1.60 (m, 2 H).

  (Scheme D) (rac)-N-(5-{(cis)-3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]cyclopentyl}-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide 67 402.1 (400 MHz, DMSO- d₆)δ ppm 12.65 (br s, 1 H), 8.49 (d, J = 4.52 Hz, 1 H), 7.77 (t, J = 7.52Hz, 1 H), 7.39 (d, J = 7.58 Hz, 1 H), 7.22-7.33 (m, 1 H), 6.97 (s, 2 H),4.00 (s, 2 H), 3.51 (br s, 1 H), 2.81- Racemic Cis 2.96 (m, 2 H), 2.21-2.44 (m, 2 H), 2.12 (d, J = 7.58 Hz, 1 H), 1.86 (d, J = 7.34 Hz, 2 H),1.37- 1.61 (m, 2 H).

  (Scheme A) N-{5-[(cis)-3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide 68* 438.2 (400 MHz, DMSO- d₆) δ ppm12.59- 12.69 (m, 1 H), 10.92-11.02 (m, 1 H), 8.45-8.52 (m, 1 H),8.14-8.26 (m, 1 H), 7.71-7.82 (m, 1 H), 7.51-7.61 (m, 1 H), 7.36-7.44(m, 1 H), 7.23-7.35 (m, 1 H), 3.96-4.04 (m, 2 H), 3.45-3.57 (m, 1 H),2.88-2.98 (m, 2 H), 2.16-2.28 (m, 2 H), 2.13 (s, 4 H), 1.76-1.90 (m, 2H), Rt (Peak 2) = 1.71 minutes Chiralpak AS-H 4.6 x 100 mm column 30%MeOH @ 120 bar CO₂, 4 mL/min. 1.43-1.61 (m, 2 H).

  (Scheme A) N-{5-[(cis)-3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4- thiadiazol-2-yl}-2-(pyridin-2-yl)acetamide 69* 438.2 (700 MHz, DMSO- d₆) δ ppm 12.67 (s, 1 H), 11.00(s, 1 H), 8.54-8.42 (m, 1 H), 8.20 (d, J = 9.1 Hz, 1 H), 7.77 (td, J =7.7, 1.9 Hz, 1 H), 7.56 (d, J = 9.1 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 1 H),7.28 (ddd, J = 7.5, 4.8, 1.2 Hz, 1 H), 4.00 (s, 2 H), 3.49 (dq, J =10.3, 8.2 Hz, 1 H), 2.93 (d, J = 7.4 Hz, 2 H), 2.43 (dt, J = 10.1, 7.5Hz, 1 H), 2.20 Rt (Peak 1) = 1.42 minutes Chiralpak AS-H 4.6 x 100 mmcolumn 30% MeOH @ 120 bar CO₂, 4 mL/min. (dt, J = 13.5, 7.1 Hz, 1 H),2.12 (s, 4 H), 1.92-1.71 (m, 2 H), 1.60-1.41 (m, 2 H).

  (Scheme A) 70 514.8 (400 MHz, DMSO- d₆) δ ppm 11.33 (m, 1 H),8.51-8.56 (m, 2 H), 8.20 (d, J = 9.2 Hz, 1 H), 7.82- 7.87 (m, 2 H), 7.59(d, J = 9.2 Hz, 1 H), 7.44-7.50 (m, 2 H), 7.35-7.42 (m, 2 H), 4.02-4.03(m, 4 H), 3.43-3.53 (m, 2 H), 2.95 (d, J = 7.6 Hz, 2 H), 2.19-2.22 (m, 2H), 1.82-1.84 (m, 2 H), 1.50-1.56 (m, 2 H). Racemic Cis(rac)-2-(pyridin-2-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2- yl}acetamide

  (Scheme A) 71* 514.8 (700 MHz, DMSO- d₆) δ ppm 11.29 (s, 1 H),8.48-8.52 (m, 2 H), 8.21 (d, J = 9.2 Hz, 1 H), 7.75- 7.79 (m, 2 H), 7.58(d, J = 9.6 Hz, 1 H), 7.38-7.42 (m, 2 H), 7.24-7.31 (m, 2 H), 4.01 (s, 3H), 3.99 (s, 3 H), 3.46-3.56 (m, 2 H), 2.96 (d, J = 6.8 Hz, 2 H), 2.15-2.25 (m, 1 H), 2.07- 2.15 (m, 1 H), 1.74- 1.93 (m, 2 H), 1.48- 1.61 (m,2 H). Rt (Peak 2) = 11.47 minutes Chiralpak OJ-H 4.6 x 150 mm column 40%MeOH @ 100 bar CO₂, 3 mL/min.2-(pyridin-2-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3- yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide

  (Scheme A) 72* 514.8 (700 MHz, DMSO- d₆) δ ppm 11.29 (s, 1 H),8.48-8.52 (m, 2 H), 8.21 (d, J = 9.2 Hz, 1 H), 7.75- 7.79 (m, 2 H), 7.58(d, J = 9.6 Hz, 1 H), 7.38-7.42 (m, 2 H), 7.24-7.31 (m, 2 H), 4.01 (s, 3H), 3.99 (s, 3 H), 3.46-3.56 (m, 2 H), 2.96 (d, J = 6.8 Hz, 2 H), 2.15-2.25 (m, 1 H), 2.07- 2.15 (m, 1 H), 1.74- 1.93 (m, 2 H), 1.48- 1.61 (m,2 H). Rt (Peak 1) = 10.82 minutes Chiralpak OJ-H 4.6 x 150 mm column 40%MeOH @ 100 bar CO₂, 3 mL/min.2-(pyridin-2-yl)-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3- yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide

73 438.1 (400 MHz, CDCl₃) δ ppm 12.63 (br s, 1 H), 8.68 (d, J = 4.8 Hz,1 H), 8.49 (br s, 1 H), 8.39 (d, J = 9.2 Hz, 1 H), 7.73 (t, J = 7.6 Hz,1 H), 7.27- 7.32 (m, 2 H), 4.01 (s, 2 H), 3.73-3.78 (m, 1 H), 3.07 (d, J= 6.8 Hz, 2 H), 2.78- 2.83 (m, 1 H), 2.60- 2.72 (m, 2 H), 2.50 (q, J =7.6 Hz, 2 H), 2.20 (q, J = 11.6 Hz, 2 H), 1.23 (t, J = 7.6 Hz, 3 H).Single dia- stereomer (Scheme A) N-{6-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclobutyl)methyl]pyridazin-3-yl}propanamide

  (Scheme A) 2-(pyridin-2-yl)-N-[6-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2- yl]cyclopentyl}methyl)pyridazin-3-yl]acetamide 74* 474.0 (400 MHz, DMSO- d₆) δ ppm 11.51 (br s, 1 H),11.29 (s, 1 H), 8.49 (d, J = 4.4 Hz, 1 H), 8.28 (d, J = 3.2 Hz, 1 H),8.21 (d, J = 9.2 Hz, 1 H), 7.72-7.76 (m, 1 H), 7.59 (d, J = 0.2 Hz, 1H), 7.39 (d, J = 8 Hz, 1 H), 7.27 (t, J = 8 Hz, 1 H), 7.07 (d, J = 8.4Hz, 1 H), 7.04 (t, J = 8 Hz, 1 H), 3.99 (s, 2 H), 3.44-3.46 (m, 2 H),2.96 (d, J = 7.6 Hz, 2 H), 2.08-2.25 (m, 2 H), 1.75-1.93 (m, 2 H),1.43-1.55 (m, 2 H). Rt (Peak 1) = 1.72 minutes Chiralpak OJ-H 4.6 x 150mm column 40% MeOH @ 100 bar CO₂, 4 mL/min.

  (Scheme A) 2-(pyridin-2-yl)-N-[6-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2- yl]cyclopentyl}methyl)pyridazin-3-yl]acetamide 75* 474.0 (400 MHz, DMSO- d₆) δ ppm 11.51 (br s, 1 H),11.29 (s, 1 H), 8.49 (d, J = 4.4 Hz, 1 H), 8.28 (d, J = 3.2 Hz, 1 H),8.21 (d, J = 9.2 Hz, 1 H), 7.72-7.76 (m, 1 H), 7.59 (d, J = 0.2 Hz, 1H), 7.39 (d, J = 8 Hz, 1 H), 7.27 (t, J = 8 Hz, 1 H), 7.07 (d, J = 8.4Hz, 1 H), 7.04 (t, J = 8 Hz, 1 H), 3.99 (s, 2 H), 3.44-3.46 (m, 2 H),2.96 (d, J = 7.6 Hz, 2 H), 2.08-2.25 (m, 2 H), 1.75-1.93 (m, 2 H),1.43-1.55 (m, 2 H). Rt (Peak 2) = 1.86 minutes Chiralpak OJ-H 4.6 x 150mm column 40% MeOH @ 100 bar CO₂, 4 mL/min.

  (Scheme A) (rac)-2-methyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide 76 466.2 (400 MHz, DMSO- d₆) δ ppm 10.90- 10.96 (m, 1 H),8.44- 8.55 (m, 1 H), 8.21 (s, 1 H), 7.71-7.83 (m, 1 H), 7.51-7.63 (m, 1H), 7.34-7.45 (m, 1 H), 7.21-7.33 (m, 1 H), 3.96 (s, 2 H), 3.41-3.56 (m,1 H), 2.94 (d, J = 7.55 Hz, 2 H), 2.72- 2.86 (m, 1 H), 2.41- 2.46 (m, 1H), 2.02- 2.28 (m, 2 H), 1.72- 1.95 (m, 2 H), 1.40- 1.64 (m, 2 H), 1.10(d, J = 6.80 Hz, 6 H). Racemic Cis

  (Scheme A) 2-methyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide 77* 466.2 (400 MHz, DMSO- d₆) δ ppm 10.90- 10.96 (m, 1H), 8.44- 8.55 (m, 1 H), 8.21 (s, 1 H), 7.71-7.83 (m, 1 H), 7.51-7.63(m, 1 H), 7.34-7.45 (m, 1 H), 7.21-7.33 (m, 1 H), 3.96 (s, 2 H),3.41-3.56 (m, 1 H), 2.94 (d, J = 7.55 Hz, 2 H), 2.72- 2.86 (m, 1 H),2.41- 2.46 (m, 1 H), 2.02- 2.28 (m, 2 H), 1.72- 1.95 (m, 2 H), 1.40-1.64 (m, 2 H), 1.10 (d, J = 6.80 Hz, 6 H). Rt (Peak 2) = 1.92 minutesChiralpak AS-H 4.6 x 100 mm column 20% MeOH (w. 0.1% DEA) @ 120 bar CO₂,4 mL/min.

  (Scheme A) 2-methyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide 78* 466.2 (400 MHz, DMSO- d₆) δ ppm 10.90- 10.96 (m, 1H), 8.44- 8.55 (m, 1 H), 8.21 (s, 1 H), 7.71-7.83 (m, 1 H), 7.51-7.63(m, 1 H), 7.34-7.45 (m, 1 H), 7.21-7.33 (m, 1 H), 3.96 (s, 2 H),3.41-3.56 (m, 1 H), 2.94 (d, J = 7.55 Hz, 2 H), 2.72- 2.86 (m, 1 H),2.41- 2.46 (m, 1 H), 2.02- 2.28 (m, 2 H), 1.72- 1.95 (m, 2 H), 1.40-1.64 (m, 2 H), 1.10 (d, J = 6.80 Hz, 6 H). Rt (Peak 1) = 2.30 minutesChiralpak AS-H 4.6 x 100 mm column 20% MeOH (w. 0.1% DEA) @ 120 bar CO₂,4 mL/min.

  (Scheme A) N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclopentyl]methyl}pyridazin-3-yl)propanamide 79* 452.0 (600 MHz, DMSO- d₆) δ ppm 10.97 (br s, 1 H),8.51 (d, J = 4.8 Hz, 1 H), 8.23 (d, J = 9.2 Hz, 1 H), 7.78-7.80 (m, 1H), 7.57 (d, J = 9.2 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.29 (t, J = 6Hz, 1 H), 4.01 (5, 2 H), 3.46-3.53 (m, 1 H), 2.94 (d, J = 7.2 Hz, 2 H),2.42 (q, J = 6.8 Hz, 2 H), 2.19- Rt (Peak 2) = 4.21 minutes ChiralpakAS-H 4.6 x 100 mm column 35% EtOH (w. 0.1% NH₃) @ 100 bar CO₂, 3 mL/min.2.23 (m, 2 H), 1.80- 1.89 (m, 2 H), 1.51- 1.56 (m, 2 H), 1.08 (t, J =7.2 Hz, 3 H).

  (Scheme A) 2-phenyl-N-(6-{[(1R,3S)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclopentyl]methyl}pyridazin-3-80 514.2 (400 MHz, DMSO- d₆) δ ppm 12.63 (br s, 1 H), 11.22 (s, 1 H),8.49 (d, J = 4.78 Hz, 1 H), 8.19 (d, J = 9.06 Hz, 1 H), 7.76 (td, J =7.68, 1.76 Hz, 1 H), 7.56 (d, J = 9.32 Hz, 1 H), 7.19-7.43 (m, 7 H),3.99 (s, 2 H), 3.76 (s, 2 H), 3.44- 3.55 (m, 1 H), 2.94 (d, J = 7.30 Hz,2 H), 1.74-1.91 (m, 2 H), 1.42-1.60 (m, 2 H). Enantio- enriched (ca. 84%ee) yl)acetamide

  (Scheme A) 2-phenyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclopentyl]methyl}pyridazin-3-81* 514.2 (400 MHz, DMSO- d₆) δ ppm 12.63 (br s, 1 H), 11.22 (s, 1 H),8.49 (d, J = 4.78 Hz, 1 H), 8.19 (d, J = 9.06 Hz, 1 H), 7.76 (td, J =7.68, 1.76 Hz, 1 H), 7.56 (d, J = 9.32 Hz, 1 H), 7.19-7.43 (m, 7 H),3.99 (s, 2 H), 3.76 (s, 2 H), 3.44- 3.55 (m, 1 H), 2.94 (d, J = 7.30 Hz,2 H), 1.74-1.91 (m, 2 H), 1.42-1.60 (m, 2 H). Rt (Peak 2) = 2.75 minutesChiralpak OJ-H 4.6 x 150 mm column 40% MeOH @ 120 bar CO₂, 4 mL/min.yl)acetamide

  (Scheme A) 2-phenyl-N-(6-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclopentyl]methyl}pyridazin-3-82 514.2 (400 MHz, DMSO- d₆) δ ppm 12.63 (br s, 1 H), 11.22 (s, 1 H),8.49 (d, J = 4.78 Hz, 1 H), 8.19 (d, J = 9.06 Hz, 1 H), 7.76 (td, J =7.68, 1.76 Hz, 1 H), 7.56 (d, J = 9.32 Hz, 1 H), 7.19-7.43 (m, 7 H),3.99 (s, 2 H), 3.76 (s, 2 H), 3.44- 3.55 (m, 1 H), 2.94 (d, J = 7.30 Hz,2 H), 1.74-1.91 (m, 2 H), 1.42-1.60 (m, 2 H). Rt (Peak 1) = 2.40 minutesChiralpak OJ-H 4.6 x 150 mm column 40% MeOH @ 120 bar CO₂, 4 mL/min.yl)acetamide

  (Scheme F) (rac)-2-(pyridin-2-yl)-N-[5-({(cis)-3-[5-(pyrimidin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2- yl]acetamide 83 480.0 (400MHz, DMSO- d₆) δ ppm 8.64- 8.65 (m, 2 H), 8.51 (s, 1 H), 7.77-7.81 (m, 1H), 7.41 (d, J = 7.2 Hz, 1 H), 7.31 (t, J = 6.4 Hz, 1 H) 7.08-7.12 (m, 1H), 4.02 (s, 2 H), 3.58- 3.61 (m, 1 H), 3.11 (d, J = 7.2 Hz, 2 H),2.15-2.41 (m, 3 H), Racemic Cis 1.81-1.91 (m, 2 H), 1.63-1.81 (m, 2 H).

  (Scheme F) 2-(pyridin-2-yl)-N-[5-({(cis)-3-[5-(pyrimidin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2- yl]acetamide 84* 480.2 (600MHz, DMSO- d₆) δ ppm 8.63 (d, J = 4.83 Hz, 1 H), 8.49 (d, J = 4.39 Hz, 1H), 7.77 (td, J = 7.68, 1.76 Hz, 1 H), 7.39 (d, J = 7.76 Hz, 1 H), 7.28(dd, J = 6.95, 5.34 Hz, 1 H) 7.06 (t, J = 4.83 Hz, 1 H), 4.00 (s, 2 H),3.42-3.56 (m, 1 H), Rt (Peak 2) = 1.61 minutes Chiralpak OJ-3 4.6 x 100mm column 40% MeOH @ 120 bar CO₂, 4 mL/min. 2.93-3.14 (m, 2 H),2.36-2.46 (m, 1 H), 2.25-2.35 (m, 1H), 2.08-2.19 (m, 1 H), 1.83-1.97 (m,2 H), 1.46-1.64 (m, 2 H).

  (Scheme F) 2-(pyridin-2-yl)-N-[5-({3-[5-(trans)(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4- thiadiazol-2-yl]acetamide 85*479.0 (700 MHz, DMSO- d₆) δ ppm 12.61 (br s, 1 H), 11.37 (br s, 1 H),8.42-8.45 (m, 1 H), 8.19-8.28 (m, 1 H), 7.64-7.71 (m, 2 H), 7.32-7.33(m, 1 H), 7.21-7.22 (m, 1 H), 6.98-6.99 (m, 1 H), 6.87-6.88 (m, 1 H),3.94 (s, 2 H), 3.50-3.54 (m, 1 H), Rt (Peak 4) = 3.76 minutes ChiralpakAS-3 4.6 x 100 mm column 40% MeOH (w. 0.1% DEA) @ 120 bar CO₂, 4 mL/min.3.00 (d, J = 7.5 Hz, 2 H), 2.12-2.14 (m, 1 H), 1.96-2.00 (m, 1 H),1.87-1.92 (m, 1 H), 1.75-1.83 (m, 3 H), 1.32-1.38 (m, 1 H).

  (Scheme F) 2-(pyridin-2-yl)-N-[5-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2- yl]acetamide 86* 479.0 (700MHz, DMSO- d₆) δ ppm 12.68 (br s, 1 H), 11.46 (br s, 1 H), 8.49-8.52 (m,1 H), 8.27-8.31 (m, 1 H), 7.71-7.78 (m, 2 H), 7.38-7.39 (m, 1 H),7.25-7.29 (m, 1 H), 7.03-7.07 (m, 1 H), 6.92-6.95 (m, 1 H), 4.00 (s, 2H), 3.57-3.61 (m, 1 H), Rt (Peak 2) = 2.44 minutes Chiralpak AS-3 4.6 x100 mm column 40% MeOH (w. 0.1% DEA) @ 120 bar CO₂, 4 mL/min. 3.04-3.07(m, 2 H), 2.16-2.24 (m, 1 H), 2.01-2.06 (m, 1 H), 1.93-1.98 (m, 1 H),1.80-1.90 (m, 2 H), 1.39-1.44 (m, 1 H).

  (Scheme F) (rac)-N-[5-({(cis)-3-[5-(pyrazin-2-ylamino)-1,3,4-thiadiazol-2- yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide 87 480.1 (400 MHz, DMSO- d₆) δ ppm 8.52(d, J = 4 Hz, 1 H), 8.47 (s, 1 H), 8.31 (s, 1 H), 8.17 (t, J = 2.8 Hz, 1H), 7.82 (t, J = 6.4 Hz, 1 H), 7.43 (d, J = 8 Hz, 1 H), 7.33 (t, J = 7.2Hz, 1 H), 4.03 (s, 2 H), 3.62-3.65 (m, 1 H), 3.07-3.11 (m, 2 H), RacemicCis 1.89-2.31 (m, 4 H), 1.46-1.60 (m, 2 H), 1.25-1.28 (m, 1 H).

  (Scheme F) (rac)-N-(5-{[(cis)-3-{5-[(1-methyl-1H-pyrazol-3-yl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)-2-(pyridin-2-yl)acetamide88** 482.2 (400 MHz, DMSO- d₆) δ ppm 12.66 (br s, 1 H), 10.66 (br s, 1H), 8.49 (d, J = 4.16 Hz, 1 H), 7.77 (td, J = 7.64, 1.71 Hz, 1 H), 7.56(d, J = 2.08 Hz, 1 H), 7.40 (d, J = 7.83 Hz, 1 H), 7.28 (dd, J = 7.09,5.14 Hz, 1 H), 5.92 (d, J = 2.20 Hz, Racemic Cis 1 H), 4.01 (s, 2 H),3.74 (s, 3 H), 3.38- 3.49 (m, 1 H), 3.06 (d, J = 1.00 Hz, 2 H),2.36-2.46 (m, 1 H), 2.21-2.32 (m, 1 H), 2.09 (m, J = 13.70, 5.50 Hz, 1H), 1.79-1.96 (m, 2 H), 1.41-1.61 (m, 2 H).

  (Scheme F) N-(5-{[(cis)-3-{5-[(1-methyl-1H-pyrazol-3-yl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)-2-(pyridin-2-yl)acetamide89* 482.2 (600 MHz, DMSO- d₆) δ ppm 10.66 (br s, 1 H), 8.48 (dt, J =4.8, 0.9 Hz, 1 H), 7.76 (td, J = 7.6, 1.8 Hz, Hz, 1 H), 7.55- 7.56 (m, 1H), 7.39 (d, J = 7.9 Hz, 1 H), 7.27-7.29 (m, 1 H), 5.91 (d, J = 2.20 Hz,1 H), 3.99 (s, 2 H), 3.73 (s, 3 H), 3.04- Rt (Peak 2) = 1.56 minutesChiralpak OJ-3 4.6 x 100 mm column 40% MeOH @ 120 bar CO₂, 4 mL/min.3.06 (m, 2 H), 2.37- 2.41 (m, 1 H), 2.23- 2.26 (m, 1 H), 2.04- 2.09 (m,1 H), 1.79- 1.90 (m, 2 H), 1.45- 1.55 (m, 2 H).

  (Scheme A) 3-methoxy-N-{5-[(cis)-3-{[6- (propanoylamino)pyridazin-3-yl]methyl}cyclopentyl]-1,3,4-thiadiazol-2- yl}propanamide 90* 419.2 (400MHz, DMSO- d₆) δ ppm 10.97 (s, 1 H), 8.24 (d, J = 8.8 Hz, 1 H), 7.58 (d,J = 9.2 Hz, 1 H), 3.63 (t, J = 6 Hz, 2 H), 3.48-3.50 (m, 1 H), 3.23 (s,3 H), 2.95 (d, J = 7.2 Hz, 2 H), 2.70 (t, J = 6.4 Hz, 2 H), 2.45-2.48(m, 3 H), 2.05-2.23 (m, 2 H), 1.49-1.91 (m, 2 H), 1.42-1.53 (m, 2 Rt(Peak 1) = 3.56 minutes Chiralpak AS-H 4.6 x 100 mm column 40% MeOH @100 bar CO₂, 3 mL/min. H), 1.08 (t, J = 7.2 Hz, 3 H).

  (Scheme A) N-(6-{[(cis)-3-(5-{[(1-methyl-1H-pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3- yl)propanamide 91* 455.2 (400 MHz,DMSO- d₆) δ ppm 10.97 (s, 1 H), 8.23 (d, J = 9.2 Hz, 1 H), 7.60 (d, J =2 Hz, 1 H), 7.57 (d, J = 9.2 Hz, 1 H), 6.15 (d, J = 2 Hz, 1 H), 3.78 (s,3 H), 3.75 (s, 2 H), 3.44- 3.48 (m, 2 H), 2.94 (d, J = 7.6 Hz, 2 H),2.44 (q, J = 7.6 Hz, 2 H), 2.02-2.23 (m, 2 H), 1.71-1.85 (m, Rt (Peak 2)= 2.19 minutes Chiralpak AS-H 4.6 x 100 mm column 40% MeOH @ 100 barCO₂, 4 mL/min. 2 H), 1.43-1.52 (m, 2 H), 1.08 (t, J = 7.6 Hz, 3 H).

  (Scheme A) N-(6-{[(cis)-3-(5-{[(1-methyl-1H-pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3- yl)propanamide 92* 455.2 (400 MHz,DMSO- d₆) δ ppm 10.97 (s, 1 H), 8.23 (d, J = 9.2 Hz, 1 H), 7.60 (d, J =2 Hz, 1 H), 7.57 (d, J = 9.2 Hz, 1 H), 6.15 (d, J = 2 Hz, 1 H), 3.78 (s,3 H), 3.75 (s, 2 H), 3.44- 3.48 (m, 2 H), 2.94 (d, J = 7.6 Hz, 2 H),2.44 (q, J = 7.6 Hz, 2 H), 2.02-2.23 (m, 2 H), 1.71-1.85 (m, Rt (Peak 1)= 2.01 minutes Chiralpak AS-H 4.6 x 100 mm column 40% MeOH @ 100 barCO₂, 4 mL/min. 2H), 1.43-1.52 (m, 2 H), 1.08 (t, J = 7.6 Hz, 3 H).

  (Scheme B) N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)diacetamide 93 379.1 (600 MHz, DMSO- d₆) δ ppm12.39 (br s, 2 H), 3.78 (quin, J = 8.48 Hz 2 H) 2.64-2.71 (m, 2 H),2.39-2.48 (m, 4 H), 2.30 (dd, J = 11.37, 8.80 Hz, 2 H), 2.17 (s, 6 H).Rt (Peak 2) = 2.20 minutes Chiralpak AS-H 4.6 x column 20% MeOH @ 120bar CO₂, 4 mL/min.

  (Scheme B) (rac)-N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2- methylpropanamide) 94 435.1 (600 MHz,DMSO- d₆) δ ppm 3.76 (quin, J = 8.45 Hz, 2 H), 2.74 (dt, J = 13.65, 6.86Hz, 2 H), 2.62-2.68 (m, 2 H), 2.37-2.47 (m, 4 H), 2.28 (dd, J = 11.20,8.85 Hz, 2 H), 1.10 (d, J = 6.88 Hz, 12 H). Racemic

  (Scheme B) N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis(2- methylpropanamide) 95 435.1 (600 MHz, DMSO-d₆) δ ppm 3.77 (quin, J = 8.45 Hz, 2 H), 2.75 (spt, J = 6.85 Hz, 2 H),2.63- 2.69 (m, 2 H), 2.38- 2.48 (m, 4 H), 2.29 (dd, J = 11.27, 8.63 Hz,2 H), 1.11 (d, J = 6.88 Hz, 12 H). Single (S) Enantiomer

  (Scheme B) (rac)-N,N-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1- methyl-1H-pyrazol-3-yl)acetamide]96 539.1 (600 MHz, DMSO- d₆) δ ppm 7.58 (d, J = 2.05 Hz, 2 H), 6.14 (d,J = 2.20 Hz, 2 H), 3.73-3.79 (m, 8 H), 3.73 (s, 4 H), 2.63-2.68 (m, 2H), 2.41-2.46 (m, 2 H), 2.39 (dd, J = 10.83, 8.78 Hz, 2 H), 2.28 Racemic(dd, J = 11.27, 8.78 Hz, 2 H).

  (Scheme B) N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1-methyl-1H- 97 539.1 (600 MHz, DMSO- d₆) δppm 7.57 (d, J = 2.05 Hz, 2 H), 6.13 (d, J = 2.20 Hz, 2 H), 3.73-3.79(m, 8 H), 3.72 (s, 4 H), 2.62-2.67 (m, 2 H), 2.36-2.45 (m, 4 H), 2.27(dd, J = 11.34, 8.71 Hz, 2 H). Single (R) Enantiomerpyrazol-3-yl)acetamide]

  (Scheme B) N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(1-methyl-1H- 98 539.1 (600 MHz, DMSO- d₆) δppm 7.58 (d, J = 1.90 Hz, 2 H), 6.14 (d, J = 2.05 Hz, 2 H), 3.74-3.80(m, 8 H), 3.73 (s, 4 H), 2.62-2.69 (m, 2 H), 2.37-2.47 (m, 4 H), 2.28(dd, J = 11.20, 8.85 Hz, 2 H). Single (S) Enantiomerpyrazol-3-yl)acetamide]

  (Scheme B) N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2- yl)acetamide] 99* 533.2 (400 MHz,DMSO- d₆) δ ppm 12.67 (br s, 2 H), 8.49 (d, J = 4.28 Hz, 2 H), 7.77 (t,J = 7.58 Hz, 2 H), 7.40 (d, J = 7.70 Hz, 2 H), 7.25-7.32 (m, 2 H), 4.01(s, 4 H), 3.78 (quin, J = 8.38 Hz, 2 H), 2.62- 2.71 (m, 2 H), 2.37- Rt(Peak 1) = 1.08 minutes Chiralpak OJ-H 4.6 x 100 mm column 40% MeOH @120 bar CO₂, 4 mL/min. 2.47 (m, 4 H), 2.25- 2.34 (m, 2 H).

100 409.0 (400 MHz, CDCl₃) δ ppm 9.04 (br s, 1 H), 8.40 (d, J = 8.8 Hz,1 H), 7.34-7.41 (m, 5 H), 7.27 (d, J = 9.2 Hz, 1 H), 5.17 (br s, 1 H),3.88 (s, 2 H), 3.53-3.62 (m, 1 H), 3.31-3.39 (m, 2 H), 3.03 (d, J = 7.2Hz, 2 H), 2.65-2.77 (m, 1 H), 2.51-2.59 (m, 2 H), 2.10 (q, J = 9.6 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3 H). Single dia- stereomer (Scheme A)N-[6-({cis-3-[5-(ethylamino)-1,3,4- thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2- phenylacetamide

  (Scheme A) 101* 424.1 (400 MHz, CD₃OD) δ ppm 8.54 (br s, 1 H), 8.40(d, J = 9.2 Hz, 1 H), 7.82-7.89 (m, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.49(d, J = 6.8 Hz, 1 H), 7.7 (t, J = 6.8 Hz, 1 H), 3.36-3.41 (m, 4 H), 3.02(d, J = 6.4 Hz, 2 H), 2.49- 2.50 (m, 1 H), 2.15- 2.27 (m, 2 H), 1.88-1.92 (m, 2 H), 1.45- 1.55 (m, 2 H), 1.26- 1.36 (m, 4 H). Rt (Peak 2) =1.54 minutes Chiralpak OJ-H 4.6 x 100 mm column 40% MeOH @ 100 bar CO₂,4 mL/min. N-[6-({(cis)-3-[5-(ethylamino)-1,3,4- thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]-2- (pyridin-2-yl)acetamide

  (Scheme B) 2-(pyridin-2-yl)-N-{5-[(1-(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)ethyl]-1,3,4- thiadiazol-2-yl}acetamide 102*521.1 (400 MHz, DMSO- d₆) δ ppm 12.66 (br s, 2 H), 8.48-8.49 (m, 2 H),7.76 (td, J = 7.70, 1.30 Hz, 2 H), 7.39 (d, J = 7.80 Hz, 2 H), 7.28 (dd,J = 7.0, 5.2 Hz, 2 H), 4.00 (d, J = 1.5 Hz, 4 H), 3.67-3.73 (m, 1 H),3.20-3.24 (m, 1 H), 2.51-2.63 (m, 2 H), 2.33-2.45 (m, 1 H), 2.05 (t, J =10.5 Hz, 2 H), 1.25 (d, J = 6.8 Hz, 3 H). Rt (Peak 2) = 0.97 minutesChiralpak OJ-H 4.6 x 100 mm column 40% MeOH @ 120 bar CO₂, 4 mL/min.

  (Scheme B) 2-(pyridin-2-yl)-N-{5-[1-(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)ethyl]-1,3,4- thiadiazol-2-yl}acetamide 103*521.1 (400 MHz, DMSO- d₆) δ ppm 12.67 (br s, 2 H), 8.49 (dd, J = 4.8,0.8 Hz, 2 H), 7.77 (td, J = 7.70, 1.70 Hz, 2 H), 7.40 (d, J = 7.80 Hz, 2H), 7.29 (dd, J = 7.2, 5.2 Hz, 2 H), 4.00 (d, J = 1.3 Hz, 4 H),3.67-3.73 (m, 1 H), 3.20-3.24 (m, 1 H), 2.51-2.63 (m, 2 H), 2.33-2.45(m, 1 H), 2.01-2.08 (m, 2 H), 1.26 (d, J = 7.0 Hz, 3H). Rt (Peak 1) =1.16 minutes Chiralpak OJ-H 4.6 x 100 mm column 40% MeOH @ 120 bar CO₂,4 mL/min.

  (Scheme C) 2-methyl-N-{5-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2- yl}propanamide 104 458.1 (600MHz, DMSO- d₆) δ ppm 8.48 (d, J = 4.83 Hz, 1 H), 7.76 (td, J = 7.68,1.76 Hz, 1 H), 7.39 (d, J = 7.76 Hz, 1 H), 7.28 (dd, J = 7.10, 5.19 Hz,1 H), 3.99 (s, 2 H), 3.74 (t, J = 8.49 Hz, 1 H), 3.11 (d, J = 7.46 Hz, 2H), 2.65- 2.80 (m, 2 H), 2.52- 2.61 (m, 2 H), 2.00- 2.12 (m, 2 H), 1.10Rt (Peak 1) = 1.94 minutes Chiralpak OJ-H 4.6 x 100 mm column 20% MeOH @120 bar CO₂, 4 mL/min (dia- stereomer separation). (d, J = 6.88 Hz, 6H).

  (Scheme C) N-{5-[cis-3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4-thiadiazol-2- yl}propanamide 105  444.10(600 MHz, DMSO- d₆) δ ppm 8.49 (d, J = 4.54 Hz, 1 H), 7.77 (t, J = 7.02Hz, 1 H), 7.39 (d, J = 7.76 Hz, 1 H), 7.25- 7.32 (m, 1 H), 4.00 (s, 2H), 3.73 (dq, J = 9.00, 8.85 Hz, 1 H), 3.12 (d, J = 7.46 Hz, 2 H), 2.69(ddd, J = 16.06, 8.41, 8.16 Hz, 1 H), 2.52- 2.59 (m, 2 H), 2.45 (q, J =7.51 Hz, 2 H), 2.01-2.11 (m, 2 H), 1.08 (t, J = 7.54 Hz, 3 H). Rt(Peak 1) = 2.15 minutes Chiralpak OJ-3 4.6 x 100 mm column 20% MeOH @120 bar CO₂, 4 mL/min (dia- stereomer separation).

  (Scheme C) 106  444.10 (600 MHz, DMSO- d₆) δ ppm 8.48 (d, J = 4.83 Hz,1 H), 7.77 (td, J = 7.65, 1.24 Hz, 1 H), 7.39 (d, J = 7.76 Hz, 1 H),7.28 (dd, J = 7.10, 5.20 Hz, 1 H), 4.00 (s, 2 H), 3.94 (t, J = 7.39 Hz,1 H), 3.23 (d, J = 7.76 Hz, 1 H), 2.71- 2.87 (m, 1 H), 2.38- 2.48 (m, 4H), 2.20- 2.34 (m, 2 H), 1.08 (t, J = 7.46 Hz, 3 H). Rt (Peak 2) = 2.55minutes Chiralpak OJ-3 4.6 x 100 mm column 20% MeOH @ 120 bar CO₂, 4mL/min (dia- stereomer separation). N-{5-[trans-3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4-thiadiazol-2- yl}propanamide

  (Scheme C) N-[5-(cis-3-{[5-(acetylamino)-1,3,4- 107 444.1 (600 MHz,DMSO- d₆) δ ppm 8.31 (s, 1 H), 7.57 (dd, J = 7.83, 1.83 Hz, 1 H), 7.27(d, J = 7.90 Hz, 1 H), 3.92 (s, 2 H), 3.64-3.80 (m, 1 H), 3.10 (d, J =7.32 Hz, 2 H) 2.68 (ddd, J = 16.17, 8.41, 8.20 Hz, 1 H), 2.51- 2.58 (m,2 H), 2.26 (s, 3 H), 2.15 (s, 3 H), 2.05 (q, J = 9.46 Hz, 2 H). Rt(Peak 1) = 0.41 minutes Chiralpak OJ-3 4.6 x 100 mm column 20% MeOH @140 bar CO₂, 4 mL/min (dia- stereomer separation).thiadiazol-2-yl]methyl}cyclobutyl)-1,3,4-thiadiazol-2-yl]-2-(5-methylpyridin-2- yl)acetamide

  (Scheme E) 2-(5-methylpyridin-2-yl)-N-(5-{[cis-3-(5-{[(5-methylpyridin-2-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide 108 535.0 (700 MHz, DMSO- d₆) δ ppm 8.31(s, 2 H), 7.57 (dd, J = 7.86, 1.54 Hz, 2 H), 7.27 (d, J = 7.86 Hz, 2 H),3.94 (d, J = 3.42 Hz, 4 H), 3.74 (m, J = 8.90, 8.90 Hz, 1 H), 3.11 (d, J= 7.34 Hz, 2 H), 2.63-2.74 (m, 1 H), 2.54 (m, J = 8.90, 2.00 Hz, 2 H),2.26 (s, 6 H), 1.97-2.11 (m, 2 H). Rt (Peak 1) = 0.75 minutes ChiralpakOJ-3 4.6 x 100 mm column 20% MeOH @ 120 bar CO₂, 3 mL/min (dia-stereomer separation).

  (Scheme E) 2-(5-methylpyridin-2-yl)-N-(5-{[trans-3-(5-{[(5-methylpyridin-2-yl)acetyl]amino}- 109 535.0 (700 MHz DMSO- d₆) δppm 12.64 (br s, 2 H), 8.31 (s, 2 H), 7.57 (d, J = 7.86 Hz, 2 H), 7.27(d, J = 7.86 Hz, 2 H), 3.87-4.00 (m, 5 H), 3.22 (d, J = 7.69 Hz, 2 H),2.73-2.83 (m, 1 H), 2.37-2.47 (m, 2 H), 2.21-2.33 (m, 8 H). Rt (Peak 2)= 0.97 minutes Chiralpak OJ-3 4.6 x 100 mm column 20% MeOH @ 120 barCO₂, 3 mL/min (dia- stereomer separation).1,3,4-thiadiazol-2-yl)cyclobutyl]methyl}-1,3,4-thiadiazol-2-yl)acetamide

  (Scheme F) N-[6-({(cis)-3-[5-(cyclopropylamino)- 1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)pyridazin-3-yl]-2- (pyridin-2-yl)acetamide 110*436.1 (400 MHz, CD₃OD) δ ppm 8.54 (d, J = 4 Hz, 1 H), 8.42 (d, J = 8 Hz,1 H), 7.85 (t, J = 4 Hz, 1 H), 7.63 (d, J = 8.8 Hz, 1 H), 7.49 (d, J =7.6 Hz, 1 H), 7.37 (t, J = 6 Hz, 1 H), 4.03 (d, J = 8.4 Hz, 2 H), 3.44(t, J = 8.8 Hz, 1 H), 3.03 (d, J = 7.6 Hz, 1 H), 2.65-2.68 (m, 1 H),2.49-2.61 (m, 1 H), 2.12-2.32 (m, Rt (Peak 2) = 4.70 minutes ChiralpakAS-H 4.6 x 100 mm column 40% MeOH @ 100 bar CO₂, 3 mL/min. 2 H),1.85-1.96 (m, 2H), 1.5-1.62 (m, 2 H), 0.79-0.82 (m, 2 H), 0.62 (br s, 2H).

  (Scheme C) 2-(5-methylpyridin-2-yl)-N-{5-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclobutyl)methyl]-1,3,4- thiadiazol-2-yl}acetamide 111521.2 (600 MHz, DMSO- d₆) δ ppm 8.72 (d, J = 4.83 Hz, 1 H), 8.55 (s, 1H), 8.00 (td, J = 7.68, 1.46 Hz, 1 H), 7.81 (dd, J = 7.76, 1.46 Hz, 1H), 7.63 (d, J = 7.76 Hz, 1 H), 7.46- 7.56 (m, 2 H), 4.24 (s, 2 H), 4.18(s, 2 H), 3.98 (t, J = 8.78 Hz, 1 H), 3.35 (d, J = 7.46 Hz, 1 H),2.87-2.97 (m, 1 H), 2.75-2.82 Rt (Peak 1) = 1.72 minutes Chiralpak OJ-34.6 x 100 mm column 30% MeOH @ 120 bar CO₂, 4 mL/min (dia- stereomerseparation). (m, 2 H), 2.74 (s, 3 H), 2.24-2.34 (m, 2 H).

  (Scheme C) 2-(5-methylpyridin-2-yl)-N-{5-[cis-3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}methyl)cyclobutyl]-1,3,4- thiadiazol-2-yl}acetamide 112521.2 (700 MHz, DMSO- d₆) δ ppm 8.48 (d, J = 4.10 Hz, 1 H), 8.31 (s, 1H), 7.76 (t, J = 7.60 Hz, 1 H), 7.57 (d, J = 7.69 Hz, 1 H), 7.39 (d, J =7.86 Hz, 1 H), 7.24- 7.30 (m, 2 H), 3.99 (s, 2 H), 3.94 (s, 2 H), 3.74(m, J = 8.70, 8.70 Hz, 1 H), 3.11 (d, J = 7.34 Hz, 2 H), 2.62-2.73 (m, 1H), 2.55 (q, J = Rt (Peak 1) = 4.03 minutes Chiralpak OJ-3 4.6 x 100 mmcolumn 20% MeOH @ 120 bar CO₂, 4 mL/min (dia- separation). stereomer8.83 Hz, 2 H), 2.05 (q, J = 9.91 Hz, 2 H).

113 409.2 (400 MHz, DMSO- d₆) δ ppm 11.26- 11.36 (m, 1 H), 8.48- 8.54(m, 1 H), 8.17- 8.26 (m, 1 H), 7.74- 7.82 (m, 1 H), 7.54- 7.65 (m, 2 H),7.35- 7.44 (m, 1 H), 7.24- 7.33 (m, 1 H), 3.99 (s, 2 H), 3.75-3.84 1 H),3.17-3.28 (m, 2 H), 3.03-3.13 (m, 2 H), 2.67-2.83 (m, 1 H), 2.13-2.37(m, 5 H), 1.15 (t, J = 6.80 Hz, 4 H). Single dia- stereomer (Scheme F)N-[6-({trans-3-[5-(ethylamino)-1,3,4- thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2- (pyridin-2-yl)acetamide

  (Scheme A) 114 409.2 (400 MHz, DMSO- d₆) δ ppm 11.02 (s, 1 H), 8.50(d, J = 4.02 Hz, 1 H), 8.21 (d, J = 9.03 Hz, 1 H), 7.78 (td, J = 7.59,1.88 Hz, 1 H), 7.55 (d, J = 9.29 Hz, 1 H), 7.40 (d, J = 7.78 Hz, 1 H),7.30 (dd, J = 7.03, 5.27 Hz, 1 H), 4.01 (s, 2 H), 3.73 (t, J = 8.41 Hz,1 H), 2.99 (d, J = 7.53 Hz, 2 H), 2.65-2.78 (m, 1 H), 2.32-2.36 (m, 1H), 2.13 (s, 3 H), 2.01- 2.11 (m, 5 H). Single dia- stereomerN-[5-(cis-3-{[6-(acetylamino)pyridazin-3-yl]methyl}cyclobutyl)-1,3,4-thiadiazol-2- yl]-2-(pyridin-2-yl)acetamide

  (Scheme A) 115 423.2 (400 MHz, DMSO- d₆) δ ppm 11.03 (s, 1 H), 8.49(d, J = 4.02 Hz, 1 H), 8.22 (d, J = 9.29 Hz, 1 H), 7.78 (td, J = 7.65,1.76 Hz, 1 H), 7.58 (d, J = 9.03 Hz, 1 H), 7.40 (d, J = 7.78 Hz, 1 H),7.29 (dd, J = 6.90, 5.14 Hz, 1 H), 3.90- 4.04 (m, 3 H), 3.11 (d, J =7.78 Hz, 2 H), 2.77-2.89 (m, 1 H), 2.65-2.72 (m, 1 H), 2.23-2.43 (m, 5H). Single dia- stereomer N-[6-({trans-3-[5-(acetylamino)-1,3,4-thiadiazol-2- yl]cyclobutyl}methyl)pyridazin-3-yl]-2-(pyridin-2-yl)acetamide

  (Scheme A) N-{5-[(cis)-3-({6-[(pyridin-2- 116* 501.0 (400 MHz, CDCl₃)δ ppm 8.75 (d, J = 4.8 Hz, 1 H), 8.70 (d, J = 4.4 Hz, 1 H), 8.57 (d, J =9.6 Hz, 1 H), 8.28 (d, J = 7.6 Hz, 1 H), 7.96-8.01 (m, 2 H), 7.53-7.64(m, 4 H), 4.29 (s, 2 H), 3.57-3.61 (m, 1 H), 3.07 (d, J = 7.2 Hz, 2 H),2.42-2.56 (m, 1 H), 2.39-2.41 (m, 1 H), 2.25-2.27 (m, 1 H), 1.95-2.05(m, 2 H), 1.71-1.73 (m, 1 H), 1.61-1.63 (m, 1 H). Rt (Peak 2) = 2.50minutes Chiralpak OJ-3 4.6 x 50 mm column 5- 40% MeOH (w. 0.05% DEA) @100 bar CO₂, 4 mL/min. ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2- yl}pyridine-2-carboxamide

  (Scheme A) N-{5-[(cis)-3-({6-[(pyridin-2- 117* 501.0 (400 MHz, CDCl₃)δ ppm 8.75 (d, J = 5.2 Hz, 1 H), 8.70 (d, J = 4.0 Hz, 1 H), 8.55 (d, J =5.6 Hz, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 7.96-8.00 (m, 2 H), 7.56-7.61(m, 2 H), 7.49-7.52 (m, 2 H), 4.26 (s, 2 H), 3.56-3.61 (m, 1 H), 3.06(d, J = 7.6 Hz, 2 H), 2.55-2.57 (m, 1 H), 2.40-2.42 (m, 1 H), 2.24-2.26(m, 1 H), 1.94-2.04 (m, 2 H), 1.61-1.73 (m, 2 H). Rt (Peak 1) = 2.26minutes Chiralpak OJ-3 4.6 x 50 mm column 5- 40% MeOH (w. 0.05% DEA) @100 bar CO₂, 4 mL/min. ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2- yl}pyridine-2-carboxamide

118 431.1 (400 MHz, DMSO- d₆) δ ppm 9.04 (s, 1 H), 8.39-8.42 (m, 1 H),7.27-7.41 (m, 6 H), 5.17 (br s, 1 H), 3.88 (s, 1 H), 3.56- 3.61 (m, 1H), 3.34- 3.35 (m, 2 H), 3.02- 3.04 (m, 2 H), 2.72- 2.76 (m, 1 H), 2.55-2.60 (m, 2 H), 1.28- 1.31 (m, 3 H). Single dia- stereomer (Scheme A)2-phenyl-N-{6-[(cis-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}cyclobutyl)methyl]pyridazin-3-yl}acetamide

  (Scheme A) N-{5-[(1S,3R)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3- 119 474.0 [M + Na]⁺ (400 MHz, CDCl₃) δ ppm8.62 (s, 1 H), 8.31 (d, J = 9.2 Hz, 1 H), 7.61-7.63 (m, 1 H), 7.24-7.26(m, 5 H), 3.90 (s, 2 H), 3.46-3.51 (m, 1 H), 2.95 (d, J = 6.8 Hz, 2 H),2.61 (d, J = 6.8 Hz, 2 H), 2.14- 2.60 (m, 4 H), 1.89- 2.01 (m, 2 H),1.58- 1.61 (m, 1 H), 1.21- 1.19 (t, J = 6.8 Hz, 3 H). Rt = 4.13 minutesChiralpak AS-H 4.6 x 150 mm column 5- 40% EtOH (w. 0.05% DEA) @ 100 barCO₂, 3 mL/min. yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2- yl}propanamide

  (Scheme A) 120 465.9 (400 MHz, CDCl₃) δ ppm 8.67 (s, 1 H), 8.36 (d, J= 8.8 Hz, 1 H), 7.67-7.69 (m, 1 H), 7.24-7.26 (m, 5 H), 3.95 (s, 2 H),3.49-3.52 (m, 1 H), 2.89-3.01 (m, 3 H), 2.19-2.55 (m, 4 H), 1.92-1.94(m, 2 H), 1.58-1.61 (m, 1 H), 1.27 (d, J = 6.4 Hz, 6H). Rt = 3.92minutes Chiralpak AS-H 4.6 x 150 mm column 5- 40% EtOH (w. 0.05% DEA) @100 bar CO₂, 3 mL/min. 2-methyl-N-{5-[(1S,3R)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3- yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propanamide

  (Scheme A) 3-methoxy-N-{5-[(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3- 121* 482.2 (400 MHz, CDCl₃) δ ppm 10.90 (brs, 1 H), 10.52 (br s, 1 H), 8.69 (d, J = 4.4 Hz, 1 H), 8.38 (d, J = 9.2Hz, 1 H), 7.69- 7.73 (m, 1 H), 7.29- 7.31 (m, 3 H), 3.95 (s, 2H),3.73-3.76 (m, 2 H), 3.51-3.54 (m, 1 H), 3.46 (s, 3 H), 3.02 (d, J = 6.8Hz, 2 H), 2.79- 2.82 (m, 2 H), 2.51- 2.53 (m, 1 H), 2.36- 2.39 (m, 1 H),2.21- 2.24 (m, 1 H), 1.94- 1.99 (m, 2 H), 1.63- 1.66 (m, 2 H). Rt (Peak2) = 1.08 minutes Chiralpak AS-3 4.6 x 50 mm column 60% IPA w. 0.05%DEA) @ 100 bar CO₂, 3 mL/min. yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}propanamide

  (Scheme A) 3-methoxy-N-{5-[(cis)-3-({6-[(pyridin-2- 122* 482.2 (400MHz, MeOD- d₄) δ ppm 8.54 (d, J = 4.4 Hz, 1 H), 8.40 (d, J = 9.2 Hz, 1H), 7.85-7.87 (m, 1 H), 7.63 (d, J = 9.6 Hz, 1 H), 7.49 (d, J = 7.6 Hz,1 H), 7.35 7.38 (m, 1 H), 3.74- 3.77 (m, 2 H), 3.55- 3.57 (m, 1 H), 3.37(s, 3 H), 3.05 (d, J = 7.6 Hz, 2 H), 2.74- 2.77 (m, 2 H), 2.55- 2.57 (m,2 H), 2.25- 2.31 (m, 2 H), 1.96- 1.98 (m, 2 H), 1.64- 1.67 (m, 2 H). Rt(Peak 1) = 0.68 minutes Chiralpak AS-3 4.6 x 50 mm column 60% IPA w.0.05% DEA) @ 100 bar CO₂, 3 mL/min. ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2- yl}propanamide

  (Scheme A) 2-(pyridin-2-yl)-N-{5-[(trans-3-{6-[(pyridin-2-ylacetyl)amino]pyridazin-3- 123 523.1 [M + Na]⁺ (400 MHz,DMSO- d₆) δ ppm 11.33 (s, 1 H), 8.50 (t, J = 5.40 Hz, 2 H), 8.22 (d, J =9.29 Hz, 1 H), 7.77 (td, J = 7.78, 1.76 Hz, 2 H), 7.63 (d, J = 9.29 Hz,1 H), 7.41 (d, J = 7.78 Hz, 2 H), 7.25- 7.33 (m, 2 H), 4.00 (s, 4 H),3.86 (s, 1 H), 3.27 (d, J = 7.78 Hz, 2 H), 2.68 (d, J = 1.76 Hz, 1 H),2.41-2.48 (m, 2 H), 2.16-2.28 (m, 2 H). Single dia- stereomeryl}cyclobutyl)methyl]-1,3,4-thiadiazol-2- yl}acetamide

  (Scheme A) 2-(pyridin-2-yl)-N-{5-[(cis-3-{6-[(pyridin- 124 523.1 [M +Na]⁺ (400 MHz, DMSO- d₆) δ ppm 11.31- 11.35 (m, 1 H),8.47- 8.53 (m, 2H), 8.20- 8.25 (m, 1 H), 7.75- 7.81 (m, 2 H), 7.62- 7.67 (m, 1 H), 7.38-7.44 (m, 2 H), 7.26- 7.32 (m, 2 H), 3.97- 4.02 (m, 4 H), 3.60- 3.67 (m,1 H), 3.41- 3.44 (m, 1 H), 3.11- 3.16 (m, 2 H), 2.65- 2.70 (m, 2 H),2.32- 2.36 (m, 1 H), 2.03- 2.11 (m, 1 H). Single dia- stereomer2-ylacetyl)amino]pyridazin-3- yl}cyclobutyl)methyl]-1,3,4-thiadiazol-2-yl}acetamide

  (Scheme A) 2-methyl-N-{6-[cis-3-({5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2- yl}methyl)cyclobutyl]pyridazin-3-yl}propanamide 125 474.0 [M + Na]⁺ (400 MHz, DMSO- d₆) δ ppm 10.96-11.02 (m, 1 H), 8.47- 8.54 (m, 1 H), 8.22- 8.30 (m, 1 H), 7.73- 7.82 (m,1 H), 7.59- 7.67 (m, 1 H), 7.38- 7.45 (m, 1 H), 7.26- 7.33 (m, 1 H),4.01 (s, 2 H), 3.83-3.90 (m, 1 H), 3.23-3.30 (m, 3 H), 2.77-2.85 (m, 1H), 2.64-2.72 (m, 1 H), 2.40-2.45 (m, 2 H), 2.32-2.37 (m, 1 H),2.17-2.28 (m, 1 H), 1.11 (d, J = 6.78 Hz, 6 H). Single dia- stereomer

  (Scheme A) 2-(1-methyl-1H-pyrazol-3-yl)-N-{5-[(cis)-3-({6-[(pyridin-2- ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2- 126* 518.1 (400 MHz, MeOD-d₄) δ ppm 8.54 (d, J = 8.8 Hz, 1 H), 8.39 (d, J = 8.8 Hz, 1 H),8.25-8.26 (m, 1 H), 7.85-7.87 (m, 1 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.55(s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.35-7.38 (m, 1 H), 6.26 (s, 1 H),3.88 (s, 3 H), 3.84 (s, 2 H), 3.54-3.58 (m, 1 H), 3.40-3.41 (m, 2 H),3.03-3.05 (d, J = 7.2 Hz, 2 H), 2.54-2.56 (m, 1 H), 2.32-2.53 (m, 1 H),2.22-2.26 (m, 1 H), 1.95-1.97(m, 2 H), 1.60-1.66 (m, 2 H). Rt (Peak 2) =5.91 minutes Chiralpak OJ-H 4.6 x 250 mm column 40% MeOH (w. 0.05% DEA)@ 100 bar CO₂, 2.4 mL/min. yl}acetamide

  (Scheme A) 2-(1-methyl-1H-pyrazol-3-yl)-N-{5-[(cis)-3-({6-[(pyridin-2- ylacetyl)amino]pyridazin-3-yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2- 127* 518.1 (400 MHz, MeOD-d₄) δ ppm 8.54 (d, J = 8.8 Hz, 1 H), 8.39 (d, J = 8.8 Hz, 1 H),8.25-8.26 (m, 1 H), 7.85-7.87 (m, 1 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.55(s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.35-7.38 (m, 1 H), 6.26 (s, 1 H),3.88 (s, 3 H), 3.84 (s, 2 H), 3.54-3.58 (m, 1 H), 3.40-3.41 (m, 2 H),3.03-3.05 (d, J = 7.2 Hz, 2 H), 2.54-2.56 (m, 1 H), 2.32-2.53 (m, 1 H),2.22-2.26 (m, 1 H), 1.95-1.97 (m, 2 H), 1.60-1.66 (m, 2 H). Rt (Peak 1)= 4.98 minutes Chiralpak OJ-H 4.6 x 250 mm column 40% MeOH (w. 0.05%DEA) @ 100 bar CO₂, 2.4 mL/min. yl}acetamide

  (Scheme A) 2-(1-methyl-1H-imidazol-4-yl)-N-{5- 128* 518.0 (400 MHz,CDCl₃) δ ppm 10.98 (s, 1 H), 8.67 (d, J = 4.8 Hz, 1 H), 8.37(d, J = 9.2Hz, 1 H), 7.68- 7.72 (m, 1 H), 7.50 (s, 1 H), 7.24-7.31 (m, 4 H), 6.83(s, 1 H), 3.98 (s, 2 H), 3.79 (s, 2 H), 3.69 (s, 3 H), 3.48 v 3.50 (m, 1H), 2.99-3.00 (d, J = 6.8 Hz, 2 H), 2.53-2.55 (m, 1 H), 2.33-2.36 (m, 1H), 2.18 (m, 1 H), 1.88- 1.96 (m, 2 H), 1.58- 1.63 (m, 2 H). Rt (Peak 1)= 1.65 minutes Chiralpak OJ-3 4.6 x 50 mm column 5- 40% MeOH (w. 0.05%DEA) @ 100 bar CO₂, 4 mL/min. [(cis)-3-({6-[(pyridin-2-ylacetyl)amino]pyridazin-3- yl}methyl)cyclopentyl]-1,3,4-thiadiazol-2-yl}acetamide

  (Scheme A) (rac)-2-(pyridin-2-yl)-N-(6-{[(cis)-3-(5-{[(2R)-tetrahydrofuran-2-ylacetyl]amino}- 1,3,4-thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3- 129 508.1 (400 MHz, MeOD- d₆) δ ppm8.54- 8.55 (m, 1 H), 8.40 (d, J = 8.8 Hz, 1 H), 7.83-7.85 (m, 1 H),7.61-7.63 (m, 1 H), 7.48-7.50 (m, 1 H), 7.35-7.37 (m, 1 H), 4.39 (s, 1H), 3.90 (s, 2 H), 3.75-3.77 (m, 1 H), 3.55-3.56 (m, 1 H), 3.33-3.35 (m,2 H), 3.03-3.04 (m, 1 H), 2.70-2.72 (m, 1 H), 2.53-2.55 (m, 1 H),2.33-2.35 (m, 1 H), 2.22-2.25 (m, 1 H), 2.13-2.15 (m, 1 H), 1.95-1.97(m, 4 H), 1.63-1.68 (m, 3 H). Racemic Cis yl)acetamide

  (Scheme A) 2-(pyridin-2-yl)-N-(6-{[(cis)-3-(5-{[(2R)-tetrahydrofuran-2-ylacetyl]amino}-1,3,4- thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3- 130* 508.2 (400 MHz, MeOD- d₆) δ ppm8.54- 8.55 (m, 1 H), 8.40 (d, J = 8.8 Hz, 1 H), 7.83-7.85 (m, 1 H),7.61-7.63 (m, 1 H), 7.48-7.50 (m, 1 H), 7.35-7.37 (m, 1 H), 4.39 (s, 1H), 3.90 (s, 2 H), 3.75-3.77 (m, 1 H), 3.55-3.56 (m, 1 H), 3.33-3.35 (m,2 H), 3.03-3.04 (m, 1 H), 2.70-2.72 (m, 1 H), 2.53-2.55 (m, 1 H),2.33-2.35 (m, 1 H), 2.22-2.25 (m, 1 H), 2.13-2.15 (m, 1 H), 1.95-1.97(m, 4 H), 1.63-1.68 (m, 3 H). Rt (Peak 2) = 1.19 minutes Chiralpak AS-34.6 x 50 mm column 60% IPA w. 0.05% DEA) @ 100 bar CO₂, 3 mL/min.yl)acetamide

  (Scheme A) 2-(pyridin-2-yl)-N-(6-{[(cis)-3-(5-{[(2R)-tetrahydrofuran-2-ylacetyl]amino}-1,3,4- thiadiazol-2-yl)cyclopentyl]methyl}pyridazin-3- 131* 508.2 (400 MHz, MeOD- d₆) δ ppm8.54- 8.55 (m, 1 H), 8.40 (d, J = 8.8 Hz, 1 H), 7.83-7.85 (m, 1 H),7.61-7.63 (m, 1 H), 7.48-7.50 (m, 1 H), 7.35-7.37 (m, 1 H), 4.39 (s, 1H), 3.90 (s, 2 H), 3.75-3.77 (m, 1 H), 3.55-3.56 (m, 1 H), 3.33-3.35 (m,2 H), 3.03-3.04 (m, 1 H), 2.70-2.72 (m, 1 H), 2.53-2.55 (m, 1 H),2.33-2.35 (m, 1 H), 2.22-2.25 (m, 1 H), 2.13-2.15 (m, 1 H), 1.95-1.97(m, 4 H), 1.63-1.68 (m, 3 H). Rt (Peak 1) = 0.91 minutes Chiralpak AS-34.6 x 50 mm column 60% IPA w. 0.05% DEA) @ 100 bar CO₂, 3 mL/min.yl)acetamide

132 445.0 (400 MHz, DMSO- d₆) δ ppm 12.35 (br s, 1 H), 11.28 (s, 1 H),8.22-8.19 (m, 1 H), 7.55-7.60 (m, 1 H), 7.26-7.37 (m, 5 H), 3.96-3.98(m, 1 H), 3.72-3.74 (m, 2 H), 3.34-3.36 (m, 1 H), 3.10-3.12 (m, 1 H),2.99-3.01 (m, 1 H), 2.68-2.69 (m, 1 H), 2.17-2.38 (m, 3 H), 2.09-2.13(m, 3 H). Single dia- stereomer (Scheme A)N-[6-({cis-3-[5-(acetylamino)-1,3,4- thiadiazol-2-yl]cyclobutyl}methyl)pyridazin-3-yl]-2- phenylacetamide

  (Scheme C) 2-(pyridin-2-yl)-N-[5-({(cis)-3-[5-(pyridin-2-ylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2- yl]acetamide 133* 479.2 (700MHz, DMSO- d₆) δ ppm 11.41 (br s, 1 H), 8.48-8.49 (m, 1 H), 8.27-8.28 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 7.5Hz, 1 H), 7.27-7.29 (m, 1 H), 7.05 (dd, J = 8.3, 0.8 Hz, 1 H), 6.95 (t,J = 6.1 Hz, 1 H), 3.47 Rt (Peak 1) = 2.38 minutes Chiralpak AS-3 4.6 x100 mm column 40% MeOH (w. 0.1% DEA) @ 120 bar CO₂, 4 mL/min (quin, J =8.5 Hz, 1H), 3.08 (d, J = 7.3 Hz, 2 H), 2.42 (dt, J = 15, 7.5 Hz, 2 H),2.25-2.32 (m, 2 H), 2.09-2.16 (m, 2 H), 1.86-1.92 (m, 2 H), 1.46-1.60(m, 2 H).

  (Scheme B) N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)dipropanamide 134 407.1 (600 MHz, DMSO- d₆) δ ppm3.76 (quin, J = 8.45 Hz, 2 H), 2.63-2.69 (m, 2 H), 2.38-2.48 (m, 8 H),2.29 (dd, J = 11.27, 8.78 Hz, 2 H), 1.08 (t, J = 7.46 Hz, 6 H). Single(S) Enantiomer

  (Scheme D) 2-methyl-N-[5-(6-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}spiro[3.3]hept-2-yl)-1,3,4-thiadiazol-2- yl]propanamide 135 484.1(600 MHz, DMSO- d₆) δ ppm 8.47 (d, J = 4.39 Hz, 1 H), 7.76 (td, J =7.68, 1.61 Hz, 1 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.28 (dd, J = 6.88, 5.12Hz, 1 H), 3.99 (s, 2 H), 3.71-3.80 (m, 2 H), 2.73 (quin, J = 6.88 Hz, 1H), 2.62-2.68 (m, 2 H), 2.35-2.46 (m, 4 H), Racemic 2.24-2.30 (m, 2 H),1.09 (d, J = 6.88 Hz, 6 H).

  (Scheme B) 2-methyl-N-{5-[6-(5-{[(1-methyl-1H-pyrazol-3-yl)acetyl]amino}-1,3,4-thiadiazol-2-yl)spiro[3.3]hept-2-yl]-1,3,4- 136 487.1 (600 MHz, DMSO-d₆) δ ppm 7.57 (s, 1 H), 6.14 (d, J = 1.90 Hz, 1 H), 3.71-3.80 (m, 7 H),2.74 (dt, J = 13.61, 6.80 Hz, 1 H), 2.63-2.68 (m, 2 H), 2.36-2.47 (m, 4H), 2.25-2.31 (m, 2 H), 1.10 (d, J = 6.88 Hz, 6 H). Racemicthiadiazol-2-yl}propanamide *Compounds are single enantiomers, however,absolute stereochemistry is unknown. (stereochemistry is depicted basedon the biological activity of a compound of known absolutestereochemistry). **Compounds are racemates containing two cisenantiomers.

TABLE 2 LCMS Example No. (Scheme) Observed Rt Structure and CompoundName MW (min) Method 137** (Scheme C)  

  (rac)-1-methyl-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-1H- pyrazole-3-carboxamide510.0 2.435 Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobile phase A: Water(w. 0.375% TFA). B: MeCN (w. 0.1875% TFA). 1 to 5% B over 0.6 mins to100% B after 4 mins. Flow rate 0.8 mL/min. API-ES positive. 138***(Scheme B)  

  N,N′-[cyclopentane-1,3-diyldi-1,3,4-thiadiazole-5,2-diyl]bis[2-(pyridin-2-yl)acetamide] 507 1.733 Xbridge C18 2.1 × 50mm (5 μm). 40° C. Mobile phase A: Water (w. 0.375% TFA). B: MeCN (w.0.1875% TFA). 1 to 5% B over 0.6 mins to 100% B after 4 mins. Flow rate0.8 mL/min. API-ES positive. 139*** (Scheme B)  

  N,N′-[cyclohexane-1,3-diyldi-1,3,4-thiadiazole-5,2-diyl]bis[2-(pyridin-2-yl)acetamide] 521 1.695 Xbridge C18 2.1 × 50mm (5 μm). 40° C. Mobile phase A: Water (w. 0.05% NH4OH). B: MeCN (w.0.1875% TFA). Initial 5% B over 0.5 mins to 100% B after 3.4 mins. Flowrate 0.8 mL/min. API-ES positive. 140*** (Scheme B)  

  N,N′-(cyclohexane-1,4-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[2-(pyridin-2-yl)acetamide] 521 1.695 Xbridge C18 2.1 × 50mm (5 μm). 40° C. Mobile phase A: Water (w. 0.05% NH₄OH). B: MeCN (w.0.1875% TFA). Initial 5% B over 0.5 mins to 100% B after 3.4 mins. Flowrate 0.8 mL/min. API-ES positive. 141*** (Scheme B)  

  N,N′-(spiro[3.3]heptane-2,6-diyldi-1,3,4-thiadiazole-5,2-diyl)diacetamide 379 1.744 Xbridge C18 2.1 × 50 mm (5μm). 40° C. Mobile phase A: Water (w. 0.375% TFA). B: MeCN (w. 0.1875%TFA). 1 to 5% B over 0.6 mins to 100% B after 4 mins. Flow rate 0.8mL/min. API-ES positive. 142** (Scheme C)  

  (rac)-2-(1H-pyrazol-1-yl)-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)acetamide 510 2.370Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobile phase A: Water (w. 0.375%TFA). B: MeCN (w. 0.1875% TFA). 1 to 5% B over 0.6 mins to 100% B after4 mins. Flow rate 0.8 mL/min. API-ES positive. 143** (Scheme C)  

  (rac)-3-(1H-pyrazol-1-yl)-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)propanamide 524 2.414Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobile phase A: Water (w. 0.375%TFA). B: MeCN (w. 0.1875% TFA). 1 to 5% B over 0.6 mins to 100% B after4 mins. Flow rate 0.8 mL/min. API-ES positive. 144** (Scheme C)  

  (rac)-2-fluoro-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)benzamide 524 2.648Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobile phase A: Water (w 0.375%TFA). B: MeCN (w 0.1875% TFA). 1 to 5% B over 0.6 mins to 100% B after 4mins. Flow rate 0.8 mL/min. API-ES positive. 145** (Scheme C)  

  (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(1,3-thiazol-4-yl)acetamide 450 2.514 Xbridge C18 2.1× 50 mm (5 μm). 40° C. Mobile phase A: Water (w 0.375% TFA). B: MeCN (w0.1875% TFA). 1 to 5% B over 0.6 mins to 100% B after 4 mins. Flow rate0.8 mL/min. API-ES positive. 146** (Scheme C)  

  (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4- thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4- thiadiazol-2-yl]-2-(1-methyl-1H-pyrazol-3-yl)acetamide 447 2.049 Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobilephase A: Water (w. 0.05% NH₄OH). B: MeCN (w. 0.1875% TFA). Initial 5% Bover 0.5 mins to 100% B after 3.4 mins. Flow rate 0.8 mL/min. API-ESpositive. 147** (Scheme C)  

  (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4- thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4- thiadiazol-2-yl]-2-(1-methyl-1H-pyrazol-3-yl)acetamide 461 2.851 Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobilephase A: Water (w. 0.375% TFA). B: MeCN (w. 0.1875% TFA). 1 to 5% B over0.6 mins to 100% B after 4 mins. Flow rate 0.8 mL/min. API-ES positive.148** (Scheme C)  

  (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4- thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4- thiadiazol-2-yl]-2-fluorobenzamide 447 2.090Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobile phase A: Water (w. 0.05%NH₄OH). B: MeCN. 5% B for 0.5 mins to 100% B after 3.4 mins holding at100% until 4.2 mins. Flow rate 0.8 mL/min. API-ES positive. 149**(Scheme C)  

  (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(imidazo[1,2-a]pyridin-2- yl)acetamide 469 2.277Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobile phase A: Water (w. 0.375%TFA). B: MeCN (w. 0.1875% TFA). 1 to 5% B over 0.6 mins to 100% B after4 mins. Flow rate 0.8 mL/min. API-ES positive. 150** (Scheme C)  

  (rac)-1-methyl-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2-yl)-1H-imidazole-4-carboxamide 510 2.272 Xbridge C18 2.1 × 50 mm (5 μm). 40° C.Mobile phase A: Water (w. 0.375% TFA). B: MeCN (w. 0.1875% TFA). 1 to 5%B over 0.6 mins to 100% B after 4 mins. Flow rate 0.8 mL/min. API-ESpositive. 151** (Scheme C)  

  (rac)-N-[5-({(cis)-3-[5-(acetylamino)-1,3,4-thiadiazol-2-yl]cyclopentyl}methyl)-1,3,4-thiadiazol-2-yl]-2-(pyridin-2-yl)acetamide 444 2.071 Xbridge C18 2.1 ×50 mm (5 μm). 40° C. Mobile phase A: Water (w 0.05% NH₄OH). B: MeCN. 5%B for 0.5 mins to 100% B after 3.4 mins. Flow rate 0.8 mL/min. API-ESpositive. 152** (Scheme B)  

  (rac)-2-(pyridin-2-yl)-N-(5-{[(cis)-3-{5-[(pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl}cyclopentyl]methyl}-1,3,4-thiadiazol-2- yl)acetamide 521 2.193Xbridge C18 2.1 × 50 mm (5 μm). 40° C. Mobile phase A: Water (w. 0.375%TFA). B: MeCN (w. 0.1875% TFA). 1 to 5% B over 0.6 mins to 100% B after4 mins. Flow rate 0.8 mL/min. API-ES positive. **Compounds are racematescontaining two cis enantiomers. ***Compounds are racemic, or mixtures ofdiastereomers obtained from commercial diacids.

Cancer Cell Lysate Total L-Glutamate Assay

Cancer cell lines (BT20, HCT116, SKOV3, HCC70, SUM149, MDA-MB-231, etc.)were plated in 96 well plates and were used for the total L-glutamateassay when the monolayer was ca. 80% confluent. The media was changedand fresh media containing L-glutamine was added to the 96 well plates,just before incubation of the cells with test compound. The testcompound was diluted in 100% DMSO using a two-fold or three-fold serialdilution. Small volumes of the dilutions of test compound were added tothe 96 well plates so the final DMSO concentration was 0.5% v/v in thecell culture medium. The cells were incubated at 37° C., 5% CO₂, and 95%air for 2 hours. Following the 2 hour incubation, the cells were washedwith water 2 times. After the last water wash, 100 μL of 50 mM Tris-HClpH 7.4 and 0.01% Tween-20 was added to each well and the plate wasfrozen at −80° C. The 96 well plate was frozen and thawed a total of 3times and then sonicated for 5 min at 4° C. in a bath sonicator.Following sonication, the 96 well plate was centrifuged for 5 min at1000 rpm and 10 μL of the supernatant was transferred to a 384 wellassay plate.

Total L-glutamate (L-glutamic acid) in the cell lysis supernatant wasdetected using glutamate oxidase, horseradish peroxidase and Amplex Redreagent (10-acetyl-3,7-dihydroxy phenoxazine, Invitrogen # A22177). Inthis assay, L-glutamate was oxidized by glutamate oxidase to producealpha-ketoglutarate (2-oxopentane dioic acid), NH₃ and H₂02. The H₂O₂(hydrogen peroxide) was used by horseradish peroxidase (HRP) to oxidizethe Amplex Red Reagent to resorufin which is a fluorescent molecule.When resorufin is excited with light with a wavelength 530-560 nm, itemits light at approximately 585 nm. For detection of total L-glutamatein 10 μL of lysate, 15 μL of an enzyme mixture was added to each well ofthe 384 well assay plate. The enzyme mixture consisted of 50 mM Tris-HClpH 7.4, 0.01% Tween-20, 50 μM Amplex Red reagent (final concentration),0.04 U/mL L-glutamate oxidase (final concentration), and 0.125 U/mL HRP(final concentration). The 384 well assay plate was incubated at roomtemperature for 5 min and then the fluorescence intensity of each wellwas measured at 585 nm using a 530-560 nm excitation wavelength in aplate based fluorimeter such as an LJL Analyst or a Tecan Infinite platereader. Standard curves were constructed for this assay using dilutionsof a L-glutamate standard. IC₅₀ were calculated by plotting the relativefluorescent units vs log of the inhibitor concentration and fitting thedata to the four parameter logistic equation.

Reference: Chapman J. and Zhou M. (1999) Microplate-based fluorometricmethods for the enzymatic determination of I-glutamate: application inmeasuring I-glutamate in food samples. Analytica Chim Acta 402:47-52.

The assay results for the compounds tested are listed in Table 3.

TABLE 3 BT20 Cell IC50 Example No. (nM) 1 0.7 2 1.0 3 6.4 4 21.6 5 104.46 N/D 7 3359.7 8 1.4 9 17.0 10 33.3 11 47.9 12 >50000.0 13 23.8 14 3.115 10.6 16 398.7 17 12.2 18 79.7 19 1467.4 20 136.7 21 >6650.5 22 1.4 239.9 24 78.9 25 1.0 26 1.3 27 241.9 28 3017.2 29 166.6 30 1.9 31 638.9 32200.9 33 7.0 34 941.5 35 50.7 36 284.0 37 19.4 38 136.0 39 N/D 40 4576.241 >40442.6 42 2373.8 43 94.4 44 5.5 45 294.7 46 349.0 47 511.5 48 989.349 788.8 50 8749.3 51 64.5 52 29.8 53 6.8 54 1276.4 55 391.1 56 2701.657 21.4 58 276.1 59 7758.6 60 274.3 61 1.6 62 38.5 63 109.8 64 71.2 651821.0 66 1287.9 67 N/D 68 7.1 69 2.5 70 0.2 71 2.7 72 0.9 73 0.7 74 3.475 1.1 76 3.0 77 0.4 78 3.0 79 1.1 80 0.1 81 4.5 82 0.1 83 2.4 84 0.5 858.2 86 4.8 87 7.5 88 13.0 89 3.9 90 1.3 91 1.5 92 0.2 93 10.4 94 8.5 951.4 96 0.3 97 2.7 98 0.5 99 0.3 100 2.4 101 338.7 102 2.0 103 0.8 1048.6 105 9.5 106 13.7 107 10.1 108 0.3 109 1.3 110 2.3 111 1.2 112 0.2113 5.6 114 6.5 115 2.0 116 5.9 117 1.4 118 0.2 119 0.2 120 0.4 121 4.0122 0.4 123 1.8 124 4.7 125 3.1 126 0.5 127 0.7 128 2.0 129 2.2 130 1.8131 3.1 132 1.7 133 1.7 134 1.3 135 2.1 136 1.9 137 4.4 138 120.3 139195.5 140 380.3 141 297.6 142 13.2 143 4.2 144 0.7 145 7.1 146 6.9 1470.5 148 12.6 149 6.9 150 1.5 151 4.6 152 2.8

We claim:
 1. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalformulation comprising at least one compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier, diluent, or excipient.